<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/NCT03294694</url>
  </required_header>
  <id_info>
    <org_study_id>17-285</org_study_id>
    <nct_id>NCT03294694</nct_id>
  </id_info>
  <brief_title>Ribociclib + PDR001 in Breast Cancer and Ovarian Cancer</brief_title>
  <official_title>A Phase 1 Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Combination With the PD-1 Inhibitor PDR001 in Patients With Metastatic Hormone Receptor-positive Breast Cancer and Metastatic Ovarian Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical trial is studying the drug Ribociclib (LEE011) in combination with an&#xD;
      immunotherapy drug called PDR001 (a therapy that uses the body's own immune system to control&#xD;
      cancer) as a possible treatment for metastatic hormone-receptor-positive (HR+), HER2-negative&#xD;
      breast cancer (in combination with fulvestrant) or metastatic epithelial ovarian cancer.&#xD;
&#xD;
      The names of the medications involved in this study are:&#xD;
&#xD;
        -  Ribociclib (LEE011)&#xD;
&#xD;
        -  PDR001&#xD;
&#xD;
        -  Fulvestrant&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      -  This research study is a Phase I clinical trial, which tests the safety of an&#xD;
           investigational combination of drugs (LEE011 with PDR001), and tries to define the&#xD;
           appropriate dose of the above combination of investigational drugs to use for further&#xD;
           studies. &quot;Investigational&quot; means that the intervention is being studied.&#xD;
&#xD;
        -  The FDA (the U.S. Food and Drug Administration) has approved LEE011 as a treatment for&#xD;
           hormone receptor positive metastatic breast cancer.&#xD;
&#xD;
        -  The FDA has not approved PDR001 as treatment for any type of cancer.&#xD;
&#xD;
        -  The FDA has approved fulvestrant as a treatment for hormone receptor positive metastatic&#xD;
           breast cancer.&#xD;
&#xD;
        -  When given separately these medications work in different ways to try and stop cancer&#xD;
           cells from growing and spreading.&#xD;
&#xD;
             -  LEE011 is a drug designed to block certain proteins called cyclin-dependent kinases&#xD;
                (CDKs) that are required for cells to divide. These proteins may also control the&#xD;
                ability of certain cancers to grow.&#xD;
&#xD;
             -  PDR001 is an antibody. Antibodies are proteins usually produced by the body that&#xD;
                help protect against foreign matter, such as bacteria and viruses. PDR001 blocks a&#xD;
                protein called PD-1 which is present on cells called T-lymphocytes, which are&#xD;
                involved in the immune response. PDR001 is being tested to see if it will allow the&#xD;
                body's immune system to work against tumor cells. Other studies have shown that&#xD;
                blocking PD-1 may result in reduced tumor cell growth in a variety of solid tumors.&#xD;
&#xD;
             -  Fulvestrant is an estrogen receptor antagonist that is indicated for the treatment&#xD;
                of postmenopausal women with HR+ MBC.&#xD;
&#xD;
        -  In this research study, the investigators are looking for a safe and tolerable dose of&#xD;
           LEE011 that can be given in combination with PDR001 for participants with metastatic&#xD;
           hormone-receptor-positive (HR+), HER2-negative breast cancer (in combination with&#xD;
           fulvestrant) or metastatic epithelial ovarian cancer.&#xD;
&#xD;
      ELIGIBILITY FOR COHORT A DOSE ESCALATION (Ribociclib + PDR001):&#xD;
&#xD;
        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO&#xD;
           CAP Guidelines.&#xD;
&#xD;
             -  Participants may have received any number of previous endocrine/hormonal lines of&#xD;
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to&#xD;
                registration.&#xD;
&#xD;
             -  Participants may have received any number of prior lines of chemotherapy for&#xD;
                advanced breast cancer as long as the last dose is ≥ 21 days prior to registration.&#xD;
&#xD;
             -  Prior therapy with biologics and investigational drugs is allowed as long as the&#xD;
                last dose is ≥ 21 days prior to registration.&#xD;
&#xD;
             -  Prior CDK4/6 inhibition is allowed. Participants who have had prior ribociclib must&#xD;
                have received treatment at full-dose without any dose-reductions. The last dose is&#xD;
                required to be ≥ 21 days prior to registration&#xD;
&#xD;
             -  No prior PD1/PDL1/CTLA4 inhibitors&#xD;
&#xD;
             -  Participants may have received radiotherapy for palliative purposes but must have&#xD;
                completed treatment ≥ 14 days prior to registration and not be experiencing &gt; grade&#xD;
                1 treatment related toxicities.&#xD;
&#xD;
             -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study&#xD;
                entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.&#xD;
&#xD;
             -  Evaluable or measurable disease by RECIST 1.1.&#xD;
&#xD;
        -  Metastatic epithelial ovarian cancer, fallopian tube or peritoneal cancer. All&#xD;
           histologies (including serous, mucinous, endometrioid, clear cell, MMMTs and mix&#xD;
           histologies) and tumor grades are eligible&#xD;
&#xD;
             -  Must have received a first-line platinum-based therapy and have disease that is&#xD;
                platinum-resistant.&#xD;
&#xD;
                --- Platinum-resistant disease is defined as disease relapse within 2 to 6 months&#xD;
                of prior platinum-based chemotherapy.&#xD;
&#xD;
             -  There is no limit to the number of lines of prior chemotherapy, biology or hormonal&#xD;
                therapy regimens.&#xD;
&#xD;
             -  No prior PD1/PDL1/CTLA4 inhibitors&#xD;
&#xD;
             -  Evaluable or measurable disease by RECIST 1.1.&#xD;
&#xD;
      ELIGIBILITY FOR COHORT A DOSE EXPANSION (Ribociclib + PDR001):&#xD;
&#xD;
        -  Metastatic epithelial ovarian cancer, fallopian tube or peritoneal cancer. All&#xD;
           histologies (including serous, mucinous, endometrioid, clear cell, MMMTs and mixed&#xD;
           histologies) and tumor grades are eligible.&#xD;
&#xD;
             -  Must have received a first-line platinum-based chemotherapy regimen and have&#xD;
                relapsed despite standard therapy.&#xD;
&#xD;
             -  Must have received a first-line platinum-based therapy and have disease that is&#xD;
                platinum-resistant.&#xD;
&#xD;
                --- Platinum-resistant disease is defined as disease relapse within 2 to 6 months&#xD;
                of prior platinum-based chemotherapy.&#xD;
&#xD;
             -  There is no limit to the number of lines of prior chemotherapy, biology or hormonal&#xD;
                therapy regimens.&#xD;
&#xD;
             -  Patients may have received any number of previous endocrine / hormonal lines of&#xD;
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to&#xD;
                first dose of study treatment.&#xD;
&#xD;
        -  Prior therapy with biologics and investigational drugs is allowed, as long as the last&#xD;
           dose is ≥ 21 days prior to first dose of study treatment.&#xD;
&#xD;
             -  No prior CDK4/6 inhibitors.&#xD;
&#xD;
             -  No prior PD1/PDL1/CTLA4 inhibitors.&#xD;
&#xD;
             -  Measurable disease by RECIST 1.1.&#xD;
&#xD;
             -  Participants with accessible tumor lesion(s) must be willing to undergo two&#xD;
                research biopsies: one prior to treatment initiation and one after 7 weeks of&#xD;
                protocol therapy. Participants who undergo an attempted on-treatment research&#xD;
                biopsy and in whom inadequate tissue is obtained are still eligible to receive&#xD;
                protocol therapy. They will not be required to undergo a repeat research biopsy&#xD;
                attempt. If a biopsy-accessible participant has had a biopsy within 30 days of&#xD;
                treatment initiation for clinical purposes, they may choose to submit an archived&#xD;
                specimen from this procedure instead.&#xD;
&#xD;
      ELIGIBILITY FOR COHORT B SAFETY RUN-IN (Ribociclib + PDR001 + Fulvestrant):&#xD;
&#xD;
        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO&#xD;
           CAP Guidelines.&#xD;
&#xD;
        -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study&#xD;
           entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.&#xD;
&#xD;
        -  Women must be postmenopausal as defined as:&#xD;
&#xD;
           -- Age &gt;60 years or Age &gt;45 with intact uterus and amenorrhea for &gt;12 consecutive months&#xD;
           or Follicle stimulating hormone (FSH) levels within postmenopausal range according to&#xD;
           the ranges established by the testing facility or Premenopausal women who have been on a&#xD;
           GnRH agonist for at least 6 weeks prior to study entry. Women in this group MUST remain&#xD;
           on the GnRH agonist for the duration of protocol treatment or Status post bilateral&#xD;
           oophorectomy, after adequate healing post-surgery&#xD;
&#xD;
        -  Evaluable or measurable disease by RECIST 1.1.&#xD;
&#xD;
        -  Prior CDK4/6 inhibition is allowed. Participants who have had prior ribociclib must have&#xD;
           received treatment at full-dose without any dose-reductions. The last dose is required&#xD;
           to be ≥ 21 days prior to registration&#xD;
&#xD;
        -  Prior hormonal therapy:&#xD;
&#xD;
             -  Prior therapy with Fulvestrant is allowed&#xD;
&#xD;
             -  Participants may have received any number of previous endocrine/hormonal lines of&#xD;
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to&#xD;
                registration.&#xD;
&#xD;
        -  Participants may have received chemotherapy for advanced breast cancer as long as the&#xD;
           last dose is ≥ 21 days prior to registration.&#xD;
&#xD;
        -  Prior therapy with biologics and investigational drugs is allowed as long as the last&#xD;
           dose is ≥ 21 days prior to registration.&#xD;
&#xD;
        -  Participants may have received radiotherapy for palliative purposes but must have&#xD;
           completed treatment ≥ 14 days prior to registration and not be experiencing &gt; grade 1&#xD;
           treatment related toxicities.&#xD;
&#xD;
      ELIGIBILITY FOR COHORT B DOSE EXPANSION (Ribociclib + PDR001 + Fulvestrant):&#xD;
&#xD;
        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO&#xD;
           CAP Guidelines.&#xD;
&#xD;
        -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study&#xD;
           entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.&#xD;
&#xD;
        -  Women must be postmenopausal as defined as:&#xD;
&#xD;
           -- Age &gt;60 years or Age &gt;45 with intact uterus and amenorrhea for &gt;12 consecutive months&#xD;
           or Follicle stimulating hormone (FSH) levels within postmenopausal range according to&#xD;
           the ranges established by the testing facility or Premenopausal women who have been on a&#xD;
           GnRH agonist for at least 6 weeks prior to study entry. Women in this group MUST remain&#xD;
           on the GnRH agonist for the duration of protocol treatment or Status post bilateral&#xD;
           oophorectomy, after adequate healing post-surgery&#xD;
&#xD;
        -  Prior hormonal therapy:&#xD;
&#xD;
             -  Participants may have received any number of previous endocrine/hormonal lines of&#xD;
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to&#xD;
                registration.&#xD;
&#xD;
             -  No prior fulvestrant&#xD;
&#xD;
        -  Participants may have received up to one prior line of chemotherapy for advanced breast&#xD;
           cancer as long as the last dose is ≥ 21 days prior to registration.&#xD;
&#xD;
        -  Prior therapy with biologics and investigational drugs is allowed as long as the last&#xD;
           dose is ≥ 21 days prior to registration.&#xD;
&#xD;
        -  No prior CDK4/6 inhibitors&#xD;
&#xD;
        -  No prior PD1/PDL1/CTLA4 inhibitors&#xD;
&#xD;
        -  Participants may have received radiotherapy for palliative purposes but must have&#xD;
           completed treatment ≥ 14 days prior to registration and not be experiencing &gt; grade 1&#xD;
           treatment-related toxicities.&#xD;
&#xD;
        -  Measurable disease by RECIST 1.1.&#xD;
&#xD;
        -  Participants with accessible tumor lesion(s) must be willing to undergo two research&#xD;
           biopsies: one prior to treatment initiation and one after 7 weeks of protocol therapy.&#xD;
           Participants who undergo an attempted on-treatment research biopsy and in whom&#xD;
           inadequate tissue is obtained are still eligible to receive protocol therapy. They will&#xD;
           not be required to undergo a repeat research biopsy attempt. If a biopsy-accessible&#xD;
           participant has had a biopsy within 30 days of treatment initiation for clinical&#xD;
           purposes, they may choose to submit an archived specimen from this procedure instead.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Safety Implications&#xD;
  </why_stopped>
  <start_date type="Actual">November 8, 2017</start_date>
  <completion_date type="Actual">October 14, 2020</completion_date>
  <primary_completion_date type="Actual">October 14, 2020</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>Cohort A: MTD/RP2D of the Combination of Ribociclib + PDR001</measure>
    <time_frame>4 weeks</time_frame>
    <description>Toxicity will be graded according to NCI CTCAE, Version 4.0.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cohort B: MTD/RP2D of the Combination of Ribociclib + PDR001 + Fulvestrant</measure>
    <time_frame>4 weeks</time_frame>
    <description>Toxicity will be graded according to NCI CTCAE, Version 4.0.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Adverse Events</measure>
    <time_frame>All participants will be evaluable for toxicity from the time of their first treatment with any study agent until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months</time_frame>
    <description>Toxicity will be graded according to NCI CTCAE, Version 4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>2 Years</time_frame>
    <description>ORR is defined as the proportion of patients with complete response or partial response by RECIST 1.1 and immune-related RECIST (irRECIST)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Metastatic Hormone-Receptor-Positive (HR+) Breast Cancer</condition>
  <condition>HER2-Negative Breast Cancer</condition>
  <condition>Metastatic Epithelial Ovarian Cancer</condition>
  <arm_group>
    <arm_group_label>Ribociclib and PDR001 (Cohort A)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The treatment regimen is defined as ribociclib + PDR001.&#xD;
Treatment will be administered on an outpatient basis.&#xD;
The study will use a 3 + 3 dose escalation design to determine the MTD/RP2D.&#xD;
Three to six evaluable patients will be enrolled in each cohort in the dose escalation phase.&#xD;
Once the RP2D of the combination of ribociclib + PDR001 is determined, there will be an expansion cohort.&#xD;
Cohort A expansion will assess the combination of ribociclib + PDR001 in 12 patients with metastatic ovarian cancer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ribociclib, PDR001 and Fulvestrant (Cohort B)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The treatment regimen is defined as ribociclib + PDR001 + fulvestrant .&#xD;
Treatment will be administered on an outpatient basis.&#xD;
There will be a safety run-in using the MTD/RP2D of ribociclib + PDR001 from Cohort A with the addition of fulvestrant in an initial 6-12 patients.&#xD;
Once the safety of the combination of ribociclib + PDR001 + fulvestrant is established, there will be an expansion cohort.&#xD;
Cohort B expansion will assess the combination of ribociclib + PDR001 + fulvestrant in 24 patients with hormone receptor-positive metastatic breast cancer (HR+ MBC).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ribociclib</intervention_name>
    <description>Each treatment cycle lasts 28 days. Ribociclib, 1 time per day by mouth for 21 days, followed by 1-week of rest (28-day cycle)</description>
    <arm_group_label>Ribociclib and PDR001 (Cohort A)</arm_group_label>
    <arm_group_label>Ribociclib, PDR001 and Fulvestrant (Cohort B)</arm_group_label>
    <other_name>Kisqali</other_name>
    <other_name>LEE011</other_name>
    <other_name>LEE-011</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PDR001</intervention_name>
    <description>Each treatment cycle lasts 28 days. (PDR001) will be administered once every 28 days (by intravenous infusion) over about 30 minutes (or up to 2 hours, if necessary) for the first infusion and over about 30 minutes for all following infusions.</description>
    <arm_group_label>Ribociclib and PDR001 (Cohort A)</arm_group_label>
    <arm_group_label>Ribociclib, PDR001 and Fulvestrant (Cohort B)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <description>Each treatment cycle lasts 28 days. Fulvestrant will be administered during Cycle 1 on days 1 and 15, and then on day 1 of each 28-day cycle thereafter.</description>
    <arm_group_label>Ribociclib, PDR001 and Fulvestrant (Cohort B)</arm_group_label>
    <other_name>Faslodex</other_name>
    <other_name>ICI 182,780</other_name>
    <other_name>ZD9238</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          -  Cohort A Dose Escalation (Ribociclib + PDR001) Eligibility can be found in Detailed&#xD;
             Description Section&#xD;
&#xD;
          -  Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant) Eligibility can be found in&#xD;
             Detailed Description Section&#xD;
&#xD;
          -  Cohort A Dose Expansion (Ribociclib + PDR001) Eligibility can be found in the Detailed&#xD;
             Description Section&#xD;
&#xD;
          -  Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant Eligibility can be found in the&#xD;
             Detailed Description Section&#xD;
&#xD;
          -  ECOG Performance Status 0-1&#xD;
&#xD;
          -  Participants must have normal organ and marrow function, as defined below:&#xD;
&#xD;
               -  absolute neutrophil count ≥1,500/mcL&#xD;
&#xD;
               -  platelets ≥100,000/mcL&#xD;
&#xD;
               -  total hemoglobin ≥ 9 g/dL (may be post-transfusion)&#xD;
&#xD;
               -  total bilirubin ≤1.5 x institutional ULN (IULN)&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) ≤2.5 × IULN or ≤5 × IULN for participants with liver&#xD;
                  metastases&#xD;
&#xD;
               -  creatinine ≤1.5 x IULN or ≥ 60 ml/min/1.73m2 for subjects with creatinine levels&#xD;
                  above institutional normal&#xD;
&#xD;
               -  INR ≤ 1.5&#xD;
&#xD;
               -  estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 by either&#xD;
                  Cockcroft-Gaultor CKD-EPI&#xD;
&#xD;
               -  baseline QTc ≤ 450 msec&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  Women of child-bearing potential, defined as all women physiologically capable of&#xD;
             becoming pregnant, must be willing to use a highly effective method of contraception&#xD;
             during dosing and for 150 days after the last dose of PDR001.&#xD;
&#xD;
        Note: Highly effective contraception methods include:&#xD;
&#xD;
          -  Total abstinence (when this is in line with the preferred and usual lifestyle of the&#xD;
             patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation&#xD;
             methods) and withdrawal are not acceptable methods of contraception&#xD;
&#xD;
          -  Female sterilization (have had surgical bilateral oophorectomy with or without&#xD;
             hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking&#xD;
             study treatment. In case of oophorectomy alone, only when the reproductive status of&#xD;
             the woman has been confirmed by follow up hormone level assessment&#xD;
&#xD;
          -  For female participants, male sterilization (at least 6 months prior to screening).&#xD;
&#xD;
          -  Placement of an intrauterine device (IUD) or intrauterine system (IUS).&#xD;
&#xD;
               -  Sexually active males must be willing to use a condom during intercourse while&#xD;
                  taking the study drug and for 21 days after stopping the study drug and should&#xD;
                  not father a child in this period. A condom is required to be used also by&#xD;
                  vasectomized men in order to prevent delivery of the drug via seminal fluid.&#xD;
&#xD;
               -  Willingness to provide archival tumor samples. If sample is not available, a&#xD;
                  biopsy should be considered in patients with safely accessible disease.&#xD;
                  Participants who undergo an attempted research biopsy procedure for the purpose&#xD;
                  of this protocol, and in whom inadequate tissue is obtained, are not required to&#xD;
                  undergo repeat biopsy in order to continue on protocol.&#xD;
&#xD;
               -  Ability to understand and the willingness to sign a written informed consent&#xD;
                  document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants cannot have been treated on a prior interventional, investigational study&#xD;
             within 2 weeks of the first dose of study treatment.&#xD;
&#xD;
          -  Participants cannot receive treatment with any other investigational agents during&#xD;
             protocol therapy.&#xD;
&#xD;
          -  Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF) ≤2&#xD;
             weeks prior start of study drug. An erythroid stimulating agent is allowed as long as&#xD;
             it was initiated at least 2 weeks prior to the first dose of study treatment.&#xD;
&#xD;
          -  History of severe hypersensitivity reactions to other mAbs&#xD;
&#xD;
          -  Participants requiring chronic treatment with systemic steroid therapy, other than&#xD;
             replacement-dose steroids in the setting of adrenal insufficiency within 7 days of&#xD;
             treatment initiation. Topical, inhaled, nasal and ophthalmic steroids are allowed.&#xD;
             Physiologic doses of steroids are acceptable.&#xD;
&#xD;
          -  Participants receiving systemic treatment with any immunosuppressive medication (other&#xD;
             than steroids as described above).&#xD;
&#xD;
          -  Patient is currently receiving warfarin or other coumadin-derived anticoagulant for&#xD;
             treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weight&#xD;
             heparin (LMWH), coumadin or fondaparinux is allowed.&#xD;
&#xD;
          -  Use of any live vaccines within 4 weeks of initiation of study treatment.&#xD;
&#xD;
          -  Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy,&#xD;
             insertion of a central venous access device, and insertion of a feeding tube are not&#xD;
             considered major surgery).&#xD;
&#xD;
          -  Participants with active autoimmune disease. Participants with vitiligo, type I&#xD;
             diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring&#xD;
             hormone replacement, psoriasis not requiring systemic treatment, or conditions not&#xD;
             expected to recur in the absence of an external trigger are permitted to enroll.&#xD;
&#xD;
          -  Presence of ≥ CTCAE grade 2 toxicity (CTCAE Grade 2 peripheral neuropathy and&#xD;
             ototoxicity and any grade alopecia are allowed).&#xD;
&#xD;
          -  Participants with uncontrolled intercurrent illness including, but not limited to:&#xD;
&#xD;
               -  Clinically significant, uncontrolled heart disease and/or cardiac repolarization&#xD;
                  abnormalities, including any of the following:&#xD;
&#xD;
                    -  History of acute coronary syndromes (including myocardial infarction,&#xD;
                       unstable angina, coronary artery bypass grafting, coronary angioplasty, or&#xD;
                       stenting) or symptomatic pericarditis within 6 months prior to screening&#xD;
&#xD;
                    -  History of documented congestive heart failure (New York Heart Association&#xD;
                       functional classification III-IV)&#xD;
&#xD;
                    -  Documented cardiomyopathy&#xD;
&#xD;
                    -  Left Ventricular Ejection Fraction (LVEF) &lt;50% as determined by Multiple&#xD;
                       Gated acquisition (MUGA) scan or echocardiogram (ECHO) within six months&#xD;
                       prior to beginning protocol therapy.&#xD;
&#xD;
                    -  Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia),&#xD;
                       complete left bundle branch block, high-grade AV block (e.g. bifascicular&#xD;
                       block, Mobitz type II and third-degree AV block)&#xD;
&#xD;
                    -  Long QT syndrome or family history of idiopathic sudden death or congenital&#xD;
                       long QT syndrome, or any of the following:&#xD;
&#xD;
                    -  Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia&#xD;
                       or hypomagnesemia, history of cardiac failure, or history of clinically&#xD;
                       significant/symptomatic bradycardia.&#xD;
&#xD;
                    -  Concomitant use of medication(s) with a known risk to prolong the QT&#xD;
                       interval and/or known to cause Torsades de Pointe that cannot be&#xD;
                       discontinued (within 5 half-lives or 7 days prior to starting study drug) or&#xD;
                       replaced by safe alternative medication&#xD;
&#xD;
                    -  Systolic blood pressure (SBP) &gt;160 mmHg or &lt;90 mmHg at screening&#xD;
&#xD;
                    -  Impairment of gastrointestinal function or who have gastrointestinal disease&#xD;
                       that may significantly alter the absorption of study drugs (e.g., ulcerative&#xD;
                       disease, uncontrolled nausea, vomiting, diarrhea or malabsorption syndrome).&#xD;
&#xD;
                    -  Patient with liver disease and Child-Pugh score B or C.&#xD;
&#xD;
               -  Individuals with a history of a second malignancy are ineligible except for the&#xD;
                  following circumstances. Individuals with a history of other malignancies are&#xD;
                  eligible if they have been disease-free for at least 5 years and are deemed by&#xD;
                  the investigator to be at low risk for recurrence of that malignancy. Individuals&#xD;
                  with the following cancers are eligible if diagnosed and treated within the past&#xD;
                  5 years: cervical cancer in situ, and non-melanoma cancer of the skin. Patients&#xD;
                  with other cancers diagnosed within the past 5 years and felt to be at low risk&#xD;
                  of recurrence should be discussed with the study sponsor to determine&#xD;
                  eligibility.&#xD;
&#xD;
               -  Participants with known brain metastases may be enrolled in this study if&#xD;
                  radiation therapy and/or surgery have been completed with a minimum of 4 weeks of&#xD;
                  stable disease demonstrated on evaluation by MRI. Such participants must no&#xD;
                  longer require treatment with corticosteroids or enzyme inducing anti-epileptic&#xD;
                  medications for their CNS disease.&#xD;
&#xD;
               -  Participants with current pneumonitis.&#xD;
&#xD;
               -  Participants known to be HIV-positive or known to have active Hepatitis B or C.&#xD;
&#xD;
               -  Pregnant or lactating women. A negative pregnancy test in women of child-bearing&#xD;
                  potential must be documented within 7 days before the first dose of study&#xD;
                  medication.&#xD;
&#xD;
               -  Any condition that would prevent the patient's participation in the clinical&#xD;
                  study due to safety concerns, compliance with clinical study procedures or&#xD;
                  interpretation of study results.&#xD;
&#xD;
               -  Active infection requiring systemic antibiotic therapy.&#xD;
&#xD;
               -  Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment.&#xD;
                  For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and&#xD;
                  nitrosoureas, 4 weeks is indicated as washout period. For patients receiving&#xD;
                  anticancer immunotherapies such as CTLA-4 antagonists, 3 weeks is indicated as&#xD;
                  the washout period&#xD;
&#xD;
               -  Participants who have received thoracic radiotherapy to lung fields ≤ 4 weeks&#xD;
                  prior to starting the study treatment or patients who have not recovered from&#xD;
                  radiotherapy-related toxicities. For all other anatomic sites (including&#xD;
                  radiotherapy to thoracic vertebrae and ribs) radiotherapy ≤ 2 weeks prior to&#xD;
                  starting the study treatment or has not recovered from radiotherapy-related&#xD;
                  toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting&#xD;
                  study treatment is allowed.&#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>Sara Tolaney, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>September 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <last_update_submitted>March 16, 2022</last_update_submitted>
  <last_update_submitted_qc>March 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Sara Tolaney</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Metastatic Hormone-Receptor-Positive (HR+) Breast Cancer</keyword>
  <keyword>HER2-Negative Breast Cancer</keyword>
  <keyword>Metastatic Epithelial Ovarian Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Ovarian Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Ovarian Epithelial</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fulvestrant</mesh_term>
    <mesh_term>Spartalizumab</mesh_term>
  </intervention_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/NCT03294694
org study id: 17-285
nct id: NCT03294694
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This clinical trial is studying the drug Ribociclib (LEE011) in combination with an
      immunotherapy drug called PDR001 (a therapy that uses the body's own immune system to control
      cancer) as a possible treatment for metastatic hormone-receptor-positive (HR+), HER2-negative
      breast cancer (in combination with fulvestrant) or metastatic epithelial ovarian cancer.

      The names of the medications involved in this study are:

        -  Ribociclib (LEE011)

        -  PDR001

        -  Fulvestrant
-  This research study is a Phase I clinical trial, which tests the safety of an
           investigational combination of drugs (LEE011 with PDR001), and tries to define the
           appropriate dose of the above combination of investigational drugs to use for further
           studies. "Investigational" means that the intervention is being studied.

        -  The FDA (the U.S. Food and Drug Administration) has approved LEE011 as a treatment for
           hormone receptor positive metastatic breast cancer.

        -  The FDA has not approved PDR001 as treatment for any type of cancer.

        -  The FDA has approved fulvestrant as a treatment for hormone receptor positive metastatic
           breast cancer.

        -  When given separately these medications work in different ways to try and stop cancer
           cells from growing and spreading.

             -  LEE011 is a drug designed to block certain proteins called cyclin-dependent kinases
                (CDKs) that are required for cells to divide. These proteins may also control the
                ability of certain cancers to grow.

             -  PDR001 is an antibody. Antibodies are proteins usually produced by the body that
                help protect against foreign matter, such as bacteria and viruses. PDR001 blocks a
                protein called PD-1 which is present on cells called T-lymphocytes, which are
                involved in the immune response. PDR001 is being tested to see if it will allow the
                body's immune system to work against tumor cells. Other studies have shown that
                blocking PD-1 may result in reduced tumor cell growth in a variety of solid tumors.

             -  Fulvestrant is an estrogen receptor antagonist that is indicated for the treatment
                of postmenopausal women with HR+ MBC.

        -  In this research study, the investigators are looking for a safe and tolerable dose of
           LEE011 that can be given in combination with PDR001 for participants with metastatic
           hormone-receptor-positive (HR+), HER2-negative breast cancer (in combination with
           fulvestrant) or metastatic epithelial ovarian cancer.

      ELIGIBILITY FOR COHORT A DOSE ESCALATION (Ribociclib + PDR001):

        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO
           CAP Guidelines.

             -  Participants may have received any number of previous endocrine/hormonal lines of
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to
                registration.

             -  Participants may have received any number of prior lines of chemotherapy for
                advanced breast cancer as long as the last dose is ≥ 21 days prior to registration.

             -  Prior therapy with biologics and investigational drugs is allowed as long as the
                last dose is ≥ 21 days prior to registration.

             -  Prior CDK4/6 inhibition is allowed. Participants who have had prior ribociclib must
                have received treatment at full-dose without any dose-reductions. The last dose is
                required to be ≥ 21 days prior to registration

             -  No prior PD1/PDL1/CTLA4 inhibitors

             -  Participants may have received radiotherapy for palliative purposes but must have
                completed treatment ≥ 14 days prior to registration and not be experiencing > grade
                1 treatment related toxicities.

             -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study
                entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.

             -  Evaluable or measurable disease by RECIST 1.1.

        -  Metastatic epithelial ovarian cancer, fallopian tube or peritoneal cancer. All
           histologies (including serous, mucinous, endometrioid, clear cell, MMMTs and mix
           histologies) and tumor grades are eligible

             -  Must have received a first-line platinum-based therapy and have disease that is
                platinum-resistant.

                --- Platinum-resistant disease is defined as disease relapse within 2 to 6 months
                of prior platinum-based chemotherapy.

             -  There is no limit to the number of lines of prior chemotherapy, biology or hormonal
                therapy regimens.

             -  No prior PD1/PDL1/CTLA4 inhibitors

             -  Evaluable or measurable disease by RECIST 1.1.

      ELIGIBILITY FOR COHORT A DOSE EXPANSION (Ribociclib + PDR001):

        -  Metastatic epithelial ovarian cancer, fallopian tube or peritoneal cancer. All
           histologies (including serous, mucinous, endometrioid, clear cell, MMMTs and mixed
           histologies) and tumor grades are eligible.

             -  Must have received a first-line platinum-based chemotherapy regimen and have
                relapsed despite standard therapy.

             -  Must have received a first-line platinum-based therapy and have disease that is
                platinum-resistant.

                --- Platinum-resistant disease is defined as disease relapse within 2 to 6 months
                of prior platinum-based chemotherapy.

             -  There is no limit to the number of lines of prior chemotherapy, biology or hormonal
                therapy regimens.

             -  Patients may have received any number of previous endocrine / hormonal lines of
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to
                first dose of study treatment.

        -  Prior therapy with biologics and investigational drugs is allowed, as long as the last
           dose is ≥ 21 days prior to first dose of study treatment.

             -  No prior CDK4/6 inhibitors.

             -  No prior PD1/PDL1/CTLA4 inhibitors.

             -  Measurable disease by RECIST 1.1.

             -  Participants with accessible tumor lesion(s) must be willing to undergo two
                research biopsies: one prior to treatment initiation and one after 7 weeks of
                protocol therapy. Participants who undergo an attempted on-treatment research
                biopsy and in whom inadequate tissue is obtained are still eligible to receive
                protocol therapy. They will not be required to undergo a repeat research biopsy
                attempt. If a biopsy-accessible participant has had a biopsy within 30 days of
                treatment initiation for clinical purposes, they may choose to submit an archived
                specimen from this procedure instead.

      ELIGIBILITY FOR COHORT B SAFETY RUN-IN (Ribociclib + PDR001 + Fulvestrant):

        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO
           CAP Guidelines.

        -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study
           entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.

        -  Women must be postmenopausal as defined as:

           -- Age >60 years or Age >45 with intact uterus and amenorrhea for >12 consecutive months
           or Follicle stimulating hormone (FSH) levels within postmenopausal range according to
           the ranges established by the testing facility or Premenopausal women who have been on a
           GnRH agonist for at least 6 weeks prior to study entry. Women in this group MUST remain
           on the GnRH agonist for the duration of protocol treatment or Status post bilateral
           oophorectomy, after adequate healing post-surgery

        -  Evaluable or measurable disease by RECIST 1.1.

        -  Prior CDK4/6 inhibition is allowed. Participants who have had prior ribociclib must have
           received treatment at full-dose without any dose-reductions. The last dose is required
           to be ≥ 21 days prior to registration

        -  Prior hormonal therapy:

             -  Prior therapy with Fulvestrant is allowed

             -  Participants may have received any number of previous endocrine/hormonal lines of
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to
                registration.

        -  Participants may have received chemotherapy for advanced breast cancer as long as the
           last dose is ≥ 21 days prior to registration.

        -  Prior therapy with biologics and investigational drugs is allowed as long as the last
           dose is ≥ 21 days prior to registration.

        -  Participants may have received radiotherapy for palliative purposes but must have
           completed treatment ≥ 14 days prior to registration and not be experiencing > grade 1
           treatment related toxicities.

      ELIGIBILITY FOR COHORT B DOSE EXPANSION (Ribociclib + PDR001 + Fulvestrant):

        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO
           CAP Guidelines.

        -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study
           entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.

        -  Women must be postmenopausal as defined as:

           -- Age >60 years or Age >45 with intact uterus and amenorrhea for >12 consecutive months
           or Follicle stimulating hormone (FSH) levels within postmenopausal range according to
           the ranges established by the testing facility or Premenopausal women who have been on a
           GnRH agonist for at least 6 weeks prior to study entry. Women in this group MUST remain
           on the GnRH agonist for the duration of protocol treatment or Status post bilateral
           oophorectomy, after adequate healing post-surgery

        -  Prior hormonal therapy:

             -  Participants may have received any number of previous endocrine/hormonal lines of
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to
                registration.

             -  No prior fulvestrant

        -  Participants may have received up to one prior line of chemotherapy for advanced breast
           cancer as long as the last dose is ≥ 21 days prior to registration.

        -  Prior therapy with biologics and investigational drugs is allowed as long as the last
           dose is ≥ 21 days prior to registration.

        -  No prior CDK4/6 inhibitors

        -  No prior PD1/PDL1/CTLA4 inhibitors

        -  Participants may have received radiotherapy for palliative purposes but must have
           completed treatment ≥ 14 days prior to registration and not be experiencing > grade 1
           treatment-related toxicities.

        -  Measurable disease by RECIST 1.1.

        -  Participants with accessible tumor lesion(s) must be willing to undergo two research
           biopsies: one prior to treatment initiation and one after 7 weeks of protocol therapy.
           Participants who undergo an attempted on-treatment research biopsy and in whom
           inadequate tissue is obtained are still eligible to receive protocol therapy. They will
           not be required to undergo a repeat research biopsy attempt. If a biopsy-accessible
           participant has had a biopsy within 30 days of treatment initiation for clinical
           purposes, they may choose to submit an archived specimen from this procedure instead.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Cohort A: MTD/RP2D of the Combination of Ribociclib + PDR001
time frame: 4 weeks
description: Toxicity will be graded according to NCI CTCAE, Version 4.0.
measure: Cohort B: MTD/RP2D of the Combination of Ribociclib + PDR001 + Fulvestrant
time frame: 4 weeks
description: Toxicity will be graded according to NCI CTCAE, Version 4.0.
measure: Number of Participants with Adverse Events
time frame: All participants will be evaluable for toxicity from the time of their first treatment with any study agent until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
description: Toxicity will be graded according to NCI CTCAE, Version 4.0.
measure: Objective Response Rate
time frame: 2 Years
description: ORR is defined as the proportion of patients with complete response or partial response by RECIST 1.1 and immune-related RECIST (irRECIST)
arm group label: Ribociclib and PDR001 (Cohort A)
arm group type: Experimental
description: The treatment regimen is defined as ribociclib + PDR001.
Treatment will be administered on an outpatient basis.
The study will use a 3 + 3 dose escalation design to determine the MTD/RP2D.
Three to six evaluable patients will be enrolled in each cohort in the dose escalation phase.
Once the RP2D of the combination of ribociclib + PDR001 is determined, there will be an expansion cohort.
Cohort A expansion will assess the combination of ribociclib + PDR001 in 12 patients with metastatic ovarian cancer.
arm group label: Ribociclib, PDR001 and Fulvestrant (Cohort B)
arm group type: Experimental
description: The treatment regimen is defined as ribociclib + PDR001 + fulvestrant .
Treatment will be administered on an outpatient basis.
There will be a safety run-in using the MTD/RP2D of ribociclib + PDR001 from Cohort A with the addition of fulvestrant in an initial 6-12 patients.
Once the safety of the combination of ribociclib + PDR001 + fulvestrant is established, there will be an expansion cohort.
Cohort B expansion will assess the combination of ribociclib + PDR001 + fulvestrant in 24 patients with hormone receptor-positive metastatic breast cancer (HR+ MBC).
intervention type: Drug
intervention name: Ribociclib
description: Each treatment cycle lasts 28 days. Ribociclib, 1 time per day by mouth for 21 days, followed by 1-week of rest (28-day cycle)
arm group label: Ribociclib and PDR001 (Cohort A)
arm group label: Ribociclib, PDR001 and Fulvestrant (Cohort B)
other name: Kisqali
other name: LEE011
other name: LEE-011
intervention type: Drug
intervention name: PDR001
description: Each treatment cycle lasts 28 days. (PDR001) will be administered once every 28 days (by intravenous infusion) over about 30 minutes (or up to 2 hours, if necessary) for the first infusion and over about 30 minutes for all following infusions.
arm group label: Ribociclib and PDR001 (Cohort A)
arm group label: Ribociclib, PDR001 and Fulvestrant (Cohort B)
intervention type: Drug
intervention name: Fulvestrant
description: Each treatment cycle lasts 28 days. Fulvestrant will be administered during Cycle 1 on days 1 and 15, and then on day 1 of each 28-day cycle thereafter.
arm group label: Ribociclib, PDR001 and Fulvestrant (Cohort B)
other name: Faslodex
other name: ICI 182,780
other name: ZD9238
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sara Tolaney, MD
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Sara Tolaney
investigator title: Principal Investigator
mesh term: Breast Neoplasms
mesh term: Ovarian Neoplasms
mesh term: Carcinoma, Ovarian Epithelial
mesh term: Fulvestrant
mesh term: Spartalizumab
sharing ipd: No