<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/NCT03233152</url>
  </required_header>
  <id_info>
    <org_study_id>2016-BN-002</org_study_id>
    <nct_id>NCT03233152</nct_id>
  </id_info>
  <brief_title>Intra-tumoral Ipilimumab Plus Intravenous Nivolumab Following the Resection of Recurrent Glioblastoma</brief_title>
  <acronym>GlitIpNi</acronym>
  <official_title>Phase I Clinical Trial on Intra-tumoral Ipilimumab Plus Intravenous Nivolumab Following the Resection of Recurrent Glioblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universitair Ziekenhuis Brussel</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Universitair Ziekenhuis Brussel</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Phase I clinical trial on intra-tumoral ipilimumab plus intravenous nivolumab following the&#xD;
      resection of recurrent glioblastoma.&#xD;
&#xD;
      The aim of this clinical trial is to exploit the potential synergy of combined intra-tumoral&#xD;
      CTLA-4 and systemic PD-1 blockade while minimizing the risk for increased immune-related&#xD;
      toxicity by intratumoral administration of the CTLA-blocking mAb ipilimumab following the&#xD;
      resection of the recurrent glioblastoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Nivolumab (OpdivoTM, BMS), a human IgG-4 mAb that blocks the Programmed cell death protein 1&#xD;
      (PD-1, CD279) has demonstrated anti-tumor activity in patients with various solid- and&#xD;
      hematological neoplasms. Nivolumab has been registered by EMA and/or FDA for the treatment of&#xD;
      patients with advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer&#xD;
      (NSCLC), and Hodgkin lymphoma. In a phase I dose escalation clinical trial, receptor blockade&#xD;
      of PD-1 by nivolumab on circulating lymphocytes was maximal at a dose of 0,3 mg/kg. In&#xD;
      patients with advanced melanoma nivolumab had a comparable tumor response rate at a dose&#xD;
      range of 0.1 to 10 mg/kg q2wks. Nivolumab was further developed at a dose of 3 mg/kg q2wks&#xD;
      and improved the overall survival of patients with advanced melanoma, NSCL, RCC and HNSCC.&#xD;
&#xD;
      Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the&#xD;
      overall survival of patients with advanced melanoma; and the relapse-free survival after&#xD;
      complete resection of high-risk stage III melanoma. Animal models have established the safety&#xD;
      and efficacy of intra-tumoral administration of ipilimumab. An intratumoral dose of CTLA-4&#xD;
      blocking mAb administered at a ratio of [1:100] compared to intravenous dosing was found to&#xD;
      result in equivalent anti-tumor effect and was associated with less systemic toxicity.&#xD;
&#xD;
      Combined treatment with ipilimumab (3 mg/kg q3wks x4) plus nivolumab (1 mg/kg q3 wks x4&#xD;
      followed by 3 mg/kg q2 wks) further increases the tumor response rate and progression-free&#xD;
      survival of patients with advanced melanoma and has been registered by EMA and FDA; this&#xD;
      combination therapy is associated with a higher incidence of immune related adverse events.&#xD;
      Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by&#xD;
      analyzing TCR usage in blood lymphocytes.&#xD;
&#xD;
      Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent&#xD;
      glioblastoma (CHECKMATE-143) were presented at the 2015 and 2016 ASCO Annual meetings (20 pts&#xD;
      were treated, 10 in each arm). [15] All nivolumab related AEs were grade 1 or 2. Eight (80%)&#xD;
      nivolumab plus ipilimumab treated patients experienced grade 3/4 AEs. Drug-related AEs&#xD;
      leading to discontinuation occurred only in nivolumab plus ipilimumab patients (n = 5; 50%),&#xD;
      including colitis, cholecystitis, diabetic ketoacidosis, confusion, and increased lipase.&#xD;
      There were no drug-related deaths. Based on these experiences, the sponsor (BMS) decided to&#xD;
      further investigate nivolumab as a mono-therapy in patients with recurrent- and newly&#xD;
      diagnosed glioblastoma (CA209-143; CA209-498 and CA209-548). Antitumor activity of nivolumab&#xD;
      has recently been established in children with recurrent glioblastoma that is characterized&#xD;
      by biallelic mismatch repair deficiency.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 17, 2016</start_date>
  <completion_date type="Anticipated">November 17, 2023</completion_date>
  <primary_completion_date type="Anticipated">November 17, 2023</primary_completion_date>
  <phase>Phase 1</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>up to 30 weeks</time_frame>
    <description>Estimate the survival of patients who are free from confirmed tumor.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>an average of 1 year</time_frame>
    <description>Estimate the survival of patients who are alive.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">6</enrollment>
  <condition>Glioblastoma</condition>
  <arm_group>
    <arm_group_label>ipilimumab + nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Only one study cohort will be predefined in this phase I clinical trial; a classical phase I &quot;3+3 patient&quot; recruitment design will be used to guide patient recruitment.&#xD;
Ipilimumab (YervoyTM, 50 mg/10 mL) will be administered by at the end of the neurosurgical resection procedure at a dose of injection of 10 mg (2 ml of YervoyTM, 50 mg/10mL vial).&#xD;
First administration of 10 mg Nivolumab (OpdivoTM, 40 mg/4mL solution) by the intravenous route will be administered within 24 hours prior to the planned neurosurgical resection. The following administrations of 10 mg nivolumab will be by a 15 minutes intravenous infusion on days 15, 29, 43, 57, and 71 (or up to ± 3 days before or after the scheduled date if necessary).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab (YervoyTM, 50 mg/10 mL solution)</intervention_name>
    <description>Ipilimumab will be administered by at the end of the neurosurgical resection procedure at a dose of injection of 10 mg (: 2 ml of YervoyTM, 50 mg/10mL vial).&#xD;
Injections will be performed manually using a 100 μ-liter dispensing syringe. Twenty needle tracks will dispense the ipilimumab solution within the brain tissue lining the resection cavity. The region suspect on preoperative MRI of the brain to be invaded by glioblastoma cells but not amenable to safe resection will be targeted by adjacent needle tracks through which up to 2 cm of depth a volume of 100 μl per needle track will be injected (: in total 20 needle tracks will be performed). This methodology has been applied previously within the context of phase III clinical trials with sitimagene ceradenovec.</description>
    <arm_group_label>ipilimumab + nivolumab</arm_group_label>
    <other_name>Nivolumab (OpdivoTM, 40 mg/4 mL solution)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab (OpdivoTM, 40 mg/4mL solution)</intervention_name>
    <description>First administration of 10 mg of nivolumab by the intravenous route should be administered within 24 hours prior to the planned neurosurgical resection. Administrations of 10 mg nivolumab (OpdivoTM, 40 mg/4mL solution) will be by a 15 minutes intravenous infusion on days 15, 29, 43, 57, and 71 (or up to ± 3 days before or after the scheduled date if necessary).</description>
    <arm_group_label>ipilimumab + nivolumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  a) Subjects must have signed and dated an approved written informed consent form in&#xD;
             accordance with regulatory and institutional guidelines. This must be obtained before&#xD;
             the performance of any protocol related procedures that are not part of normal subject&#xD;
             care b) Subjects must be willing and able to comply with scheduled visits, treatment&#xD;
             schedule, laboratory tests, tumor biopsies, and other requirements of the study.&#xD;
&#xD;
             c) Histopathological diagnosis of glioblastoma (= WHO grade IV glioma of the central&#xD;
             nervous system); both patients with &quot;de novo&quot; and &quot;secondary&quot; glioblastoma are&#xD;
             eligible; patients who have histological proof of a lower-grade glioma (WHO grade I,&#xD;
             II or III) and have evidence for transformation to WHO-grade IV glioma on imaging of&#xD;
             the brain are eligible for study participation; d) Diagnosis of glioblastoma&#xD;
             recurrence and/or progression following prior treatment with surgery, radiation&#xD;
             therapy and temozolomide chemotherapy (recurrence/progression is defined as&#xD;
             significant [according to the investigators assessment] growth and/or recurrence of&#xD;
             the glioblastoma tumor mass on sequential MRI of the brain); e) The following disease&#xD;
             characteristics should be present:&#xD;
&#xD;
               -  Presence of a measurable tumor lesion that is characterized by gadolinium&#xD;
                  enhancement on T1-MRI of the brain (with a longest diameter of &gt; 10 mm and a&#xD;
                  perpendicular diameter of &gt;5mm);&#xD;
&#xD;
               -  No evidence of clinically relevant spontaneous intra-tumor hemorrhage on baseline&#xD;
                  MRI-imaging or in the prior disease history; f) No contraindication for&#xD;
                  evaluation by gadolinium enhanced MRI pr FET-PET of the brain; g) ECOG&#xD;
                  performance status score of 0, 1 or 2; h) An interval of at least 4 months (: 16&#xD;
                  weeks) after the end of postoperative radiation therapy for glioblastoma unless&#xD;
                  progression is confirmed on an MRI of the brain obtained &gt; 4 week after the first&#xD;
                  observation of progression; and with an interval of at least 4 weeks after the&#xD;
                  last administration of temozolomide; i) No contra-indication for neurosurgical&#xD;
                  resection of the glioblastoma recurrence; j) Male or female, 18 years of age or&#xD;
                  older; k) Resolution of all acute toxic effects of prior surgical procedures,&#xD;
                  radiotherapy and temozolomide to NCI CTCAEv4.0 grade 0 or 1 except for alopecia;&#xD;
                  l) Adequate organ function as defined by the following criteria:&#xD;
&#xD;
               -  Total serum bilirubin &lt; 1.5 x ULN (patients with Gilbert's disease exempt who&#xD;
                  should have bilirubin &lt; 2x ULN)&#xD;
&#xD;
               -  AST and ALT &lt; 2.5 x upper limit of normal (ULN);&#xD;
&#xD;
               -  Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt; 1500/mm³ without growth factor support&#xD;
&#xD;
               -  Platelets &gt; 75 000 cells/mm³&#xD;
&#xD;
               -  Hemoglobin ≥9 g/dL (which may be obtained by transfusion or growth factor&#xD;
                  support)&#xD;
&#xD;
               -  FT4 hormone levels within normal range&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  prior treatment on a nivolumab and/or ipilimumab trial;&#xD;
&#xD;
          -  prior treatment with an anti-CTLA-4 or anti-PD1:-L1 targeted therapy;&#xD;
&#xD;
          -  gastrointestinal abnormalities including:&#xD;
&#xD;
          -  Inability to take oral medication.&#xD;
&#xD;
          -  Requirement for intravenous alimentation.&#xD;
&#xD;
               -  Prior surgical procedures affecting absorption including gastric resection.&#xD;
&#xD;
               -  Treatment for active peptic ulcer disease in the past 6 months.&#xD;
&#xD;
               -  Malabsorption syndromes.&#xD;
&#xD;
               -  Active gastrointestinal bleeding, unrelated to cancer, as evidenced by&#xD;
                  hematemesis, hematochezia or melena in the past 3 months without evidence of&#xD;
                  resolution documented by endoscopy or colonoscopy;&#xD;
&#xD;
          -  evidence of pre-existing uncontrolled hypertension as documented by 2 baseline blood&#xD;
             pressure readings taken at least 1 hour apart. The baseline systolic blood pressure&#xD;
             readings must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must&#xD;
             be ≤90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies&#xD;
             are eligible;&#xD;
&#xD;
          -  concurrent treatment:&#xD;
&#xD;
               -  In another therapeutic clinical trial;&#xD;
&#xD;
               -  No requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose&#xD;
                  anticoagulants for maintenance of patency of central venous access devise or&#xD;
                  prevention of deep venous thrombosis is not allowed. Therapeutic use of low&#xD;
                  molecular weight heparin is not allowed.&#xD;
&#xD;
          -  Subjects with active, known, or suspected autoimmune disease are not eligible.&#xD;
             Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune&#xD;
             thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo,&#xD;
             psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.&#xD;
&#xD;
          -  Subjects requiring systemic treatment with either corticosteroids (&gt; 16 mg daily&#xD;
             methylprednisolone equivalent) or other immunosuppressive medications within 14 days&#xD;
             of study enrollment. Inhaled or topical steroids are permitted in the absence of&#xD;
             active autoimmune disease.&#xD;
&#xD;
          -  active uncontrolled seizure disorder.&#xD;
&#xD;
          -  myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass&#xD;
             graft, symptomatic congestive heart failure or any unstable arrhythmia,&#xD;
             cerebrovascular accident or transient ischemic attack, within the 12 months prior to&#xD;
             study drug administration. No current or recent (within 1 month) use of a thrombolytic&#xD;
             agent or a thrombo-embolic event;&#xD;
&#xD;
          -  known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome&#xD;
             (AIDS)-related illness;&#xD;
&#xD;
          -  serious uncontrolled medical disorder or active infection that would impair their&#xD;
             ability to receive study treatment;&#xD;
&#xD;
          -  history of a malignancy (other than glioma) except those treated with curative intent&#xD;
             for skin cancer (other than melanoma) or in situ breast or cervical cancer or those&#xD;
             treated with curative intent for any other cancer with no evidence of disease for 5&#xD;
             years;&#xD;
&#xD;
          -  other severe acute or chronic medical or psychiatric condition, or laboratory&#xD;
             abnormality that would impart, in the judgment of the investigator, excess risk&#xD;
             associated with study participation or study drug administration, or which, in the&#xD;
             judgment of the investigator, would make the patient inappropriate for entry into this&#xD;
             study;&#xD;
&#xD;
          -  dementia or significantly altered mental status that would prohibit the understanding&#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_contact>
    <last_name>Prof. Dr. Bart Neyns, MD, PhD</last_name>
    <phone>+3224775447</phone>
    <email>Bart.Neyns@uzbrussel.be</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Dr. Johnny Deurinck, MD, PhD</last_name>
    <phone>+3224775514</phone>
    <email>Johnny.Duerinck@uzbrussel.be</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Universitair Ziekenhuis Brussel</name>
      <address>
        <city>Brussels</city>
        <zip>1090</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Prof. Dr. Bart Neyns, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Dr. Johnny Deurinck, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <reference>
    <citation>Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Sep 24;373(13):1270-1. doi: 10.1056/NEJMc1509660. No abstract available. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.</citation>
    <PMID>26398076</PMID>
  </reference>
  <reference>
    <citation>Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. doi: 10.1056/NEJMoa1414428. Epub 2015 Apr 20. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.</citation>
    <PMID>25891304</PMID>
  </reference>
  <reference>
    <citation>Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.</citation>
    <PMID>26028407</PMID>
  </reference>
  <reference>
    <citation>Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol. 2015 May 1;33(13):1430-7. doi: 10.1200/JCO.2014.59.0703. Epub 2014 Dec 1.</citation>
    <PMID>25452452</PMID>
  </reference>
  <reference>
    <citation>Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2.</citation>
    <PMID>22658128</PMID>
  </reference>
  <reference>
    <citation>Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014 Apr 1;32(10):1020-30. doi: 10.1200/JCO.2013.53.0105. Epub 2014 Mar 3.</citation>
    <PMID>24590637</PMID>
  </reference>
  <reference>
    <citation>Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5. Erratum In: N Engl J Med. 2010 Sep 23;363(13):1290.</citation>
    <PMID>20525992</PMID>
  </reference>
  <reference>
    <citation>Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. doi: 10.1016/S1470-2045(15)70122-1. Epub 2015 Mar 31. Erratum In: Lancet Oncol. 2015 Jun;16(6):e262. Lancet Oncol. 2016 Jun;17 (6):e223.</citation>
    <PMID>25840693</PMID>
  </reference>
  <reference>
    <citation>Fransen MF, van der Sluis TC, Ossendorp F, Arens R, Melief CJ. Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects. Clin Cancer Res. 2013 Oct 1;19(19):5381-9. doi: 10.1158/1078-0432.CCR-12-0781. Epub 2013 Jun 20.</citation>
    <PMID>23788581</PMID>
  </reference>
  <reference>
    <citation>Marabelle A, Kohrt H, Levy R. Intratumoral anti-CTLA-4 therapy: enhancing efficacy while avoiding toxicity. Clin Cancer Res. 2013 Oct 1;19(19):5261-3. doi: 10.1158/1078-0432.CCR-13-1923. Epub 2013 Aug 21.</citation>
    <PMID>23965900</PMID>
  </reference>
  <reference>
    <citation>Robert L, Harview C, Emerson R, Wang X, Mok S, Homet B, Comin-Anduix B, Koya RC, Robins H, Tumeh PC, Ribas A. Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes. Oncoimmunology. 2014 Jun 25;3:e29244. doi: 10.4161/onci.29244. eCollection 2014.</citation>
    <PMID>25083336</PMID>
  </reference>
  <reference>
    <citation>Preusser M, Lim M, Hafler DA, Reardon DA, Sampson JH. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol. 2015 Sep;11(9):504-14. doi: 10.1038/nrneurol.2015.139. Epub 2015 Aug 11.</citation>
    <PMID>26260659</PMID>
  </reference>
  <reference>
    <citation>Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, Durno C, Krueger J, Cabric V, Ramaswamy V, Zhukova N, Mason G, Farah R, Afzal S, Yalon M, Rechavi G, Magimairajan V, Walsh MF, Constantini S, Dvir R, Elhasid R, Reddy A, Osborn M, Sullivan M, Hansford J, Dodgshun A, Klauber-Demore N, Peterson L, Patel S, Lindhorst S, Atkinson J, Cohen Z, Laframboise R, Dirks P, Taylor M, Malkin D, Albrecht S, Dudley RW, Jabado N, Hawkins CE, Shlien A, Tabori U. Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. J Clin Oncol. 2016 Jul 1;34(19):2206-11. doi: 10.1200/JCO.2016.66.6552. Epub 2016 Mar 21.</citation>
    <PMID>27001570</PMID>
  </reference>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>July 17, 2017</study_first_submitted>
  <study_first_submitted_qc>July 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 28, 2017</study_first_posted>
  <last_update_submitted>December 16, 2020</last_update_submitted>
  <last_update_submitted_qc>December 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Universitair Ziekenhuis Brussel</investigator_affiliation>
    <investigator_full_name>Bart Neyns</investigator_full_name>
    <investigator_title>Head of Medical Oncology</investigator_title>
  </responsible_party>
  <keyword>recurrence</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
    <mesh_term>Pharmaceutical Solutions</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/NCT03233152
org study id: 2016-BN-002
nct id: NCT03233152
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
Phase I clinical trial on intra-tumoral ipilimumab plus intravenous nivolumab following the
      resection of recurrent glioblastoma.

      The aim of this clinical trial is to exploit the potential synergy of combined intra-tumoral
      CTLA-4 and systemic PD-1 blockade while minimizing the risk for increased immune-related
      toxicity by intratumoral administration of the CTLA-blocking mAb ipilimumab following the
      resection of the recurrent glioblastoma.
Nivolumab (OpdivoTM, BMS), a human IgG-4 mAb that blocks the Programmed cell death protein 1
      (PD-1, CD279) has demonstrated anti-tumor activity in patients with various solid- and
      hematological neoplasms. Nivolumab has been registered by EMA and/or FDA for the treatment of
      patients with advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer
      (NSCLC), and Hodgkin lymphoma. In a phase I dose escalation clinical trial, receptor blockade
      of PD-1 by nivolumab on circulating lymphocytes was maximal at a dose of 0,3 mg/kg. In
      patients with advanced melanoma nivolumab had a comparable tumor response rate at a dose
      range of 0.1 to 10 mg/kg q2wks. Nivolumab was further developed at a dose of 3 mg/kg q2wks
      and improved the overall survival of patients with advanced melanoma, NSCL, RCC and HNSCC.

      Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the
      overall survival of patients with advanced melanoma; and the relapse-free survival after
      complete resection of high-risk stage III melanoma. Animal models have established the safety
      and efficacy of intra-tumoral administration of ipilimumab. An intratumoral dose of CTLA-4
      blocking mAb administered at a ratio of [1:100] compared to intravenous dosing was found to
      result in equivalent anti-tumor effect and was associated with less systemic toxicity.

      Combined treatment with ipilimumab (3 mg/kg q3wks x4) plus nivolumab (1 mg/kg q3 wks x4
      followed by 3 mg/kg q2 wks) further increases the tumor response rate and progression-free
      survival of patients with advanced melanoma and has been registered by EMA and FDA; this
      combination therapy is associated with a higher incidence of immune related adverse events.
      Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by
      analyzing TCR usage in blood lymphocytes.

      Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent
      glioblastoma (CHECKMATE-143) were presented at the 2015 and 2016 ASCO Annual meetings (20 pts
      were treated, 10 in each arm). [15] All nivolumab related AEs were grade 1 or 2. Eight (80%)
      nivolumab plus ipilimumab treated patients experienced grade 3/4 AEs. Drug-related AEs
      leading to discontinuation occurred only in nivolumab plus ipilimumab patients (n = 5; 50%),
      including colitis, cholecystitis, diabetic ketoacidosis, confusion, and increased lipase.
      There were no drug-related deaths. Based on these experiences, the sponsor (BMS) decided to
      further investigate nivolumab as a mono-therapy in patients with recurrent- and newly
      diagnosed glioblastoma (CA209-143; CA209-498 and CA209-548). Antitumor activity of nivolumab
      has recently been established in children with recurrent glioblastoma that is characterized
      by biallelic mismatch repair deficiency.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free survival (PFS)
time frame: up to 30 weeks
description: Estimate the survival of patients who are free from confirmed tumor.
measure: Overall Survival (OS)
time frame: an average of 1 year
description: Estimate the survival of patients who are alive.
arm group label: ipilimumab + nivolumab
arm group type: Experimental
description: Only one study cohort will be predefined in this phase I clinical trial; a classical phase I "3+3 patient" recruitment design will be used to guide patient recruitment.
Ipilimumab (YervoyTM, 50 mg/10 mL) will be administered by at the end of the neurosurgical resection procedure at a dose of injection of 10 mg (2 ml of YervoyTM, 50 mg/10mL vial).
First administration of 10 mg Nivolumab (OpdivoTM, 40 mg/4mL solution) by the intravenous route will be administered within 24 hours prior to the planned neurosurgical resection. The following administrations of 10 mg nivolumab will be by a 15 minutes intravenous infusion on days 15, 29, 43, 57, and 71 (or up to ± 3 days before or after the scheduled date if necessary).
intervention type: Drug
intervention name: Ipilimumab (YervoyTM, 50 mg/10 mL solution)
description: Ipilimumab will be administered by at the end of the neurosurgical resection procedure at a dose of injection of 10 mg (: 2 ml of YervoyTM, 50 mg/10mL vial).
Injections will be performed manually using a 100 μ-liter dispensing syringe. Twenty needle tracks will dispense the ipilimumab solution within the brain tissue lining the resection cavity. The region suspect on preoperative MRI of the brain to be invaded by glioblastoma cells but not amenable to safe resection will be targeted by adjacent needle tracks through which up to 2 cm of depth a volume of 100 μl per needle track will be injected (: in total 20 needle tracks will be performed). This methodology has been applied previously within the context of phase III clinical trials with sitimagene ceradenovec.
arm group label: ipilimumab + nivolumab
other name: Nivolumab (OpdivoTM, 40 mg/4 mL solution)
intervention type: Drug
intervention name: Nivolumab (OpdivoTM, 40 mg/4mL solution)
description: First administration of 10 mg of nivolumab by the intravenous route should be administered within 24 hours prior to the planned neurosurgical resection. Administrations of 10 mg nivolumab (OpdivoTM, 40 mg/4mL solution) will be by a 15 minutes intravenous infusion on days 15, 29, 43, 57, and 71 (or up to ± 3 days before or after the scheduled date if necessary).
arm group label: ipilimumab + nivolumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Prof. Dr. Bart Neyns, MD, PhD
phone: +3224775447
email: Bart.Neyns@uzbrussel.be
last name: Dr. Johnny Deurinck, MD, PhD
phone: +3224775514
email: Johnny.Duerinck@uzbrussel.be
facility: 
status: Recruiting
investigator: 
investigator: 
country: Belgium
citation: Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Sep 24;373(13):1270-1. doi: 10.1056/NEJMc1509660. No abstract available. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.
PMID: 26398076
citation: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. doi: 10.1056/NEJMoa1414428. Epub 2015 Apr 20. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.
PMID: 25891304
citation: Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.
PMID: 26028407
citation: Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol. 2015 May 1;33(13):1430-7. doi: 10.1200/JCO.2014.59.0703. Epub 2014 Dec 1.
PMID: 25452452
citation: Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2.
PMID: 22658128
citation: Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014 Apr 1;32(10):1020-30. doi: 10.1200/JCO.2013.53.0105. Epub 2014 Mar 3.
PMID: 24590637
citation: Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5. Erratum In: N Engl J Med. 2010 Sep 23;363(13):1290.
PMID: 20525992
citation: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. doi: 10.1016/S1470-2045(15)70122-1. Epub 2015 Mar 31. Erratum In: Lancet Oncol. 2015 Jun;16(6):e262. Lancet Oncol. 2016 Jun;17 (6):e223.
PMID: 25840693
citation: Fransen MF, van der Sluis TC, Ossendorp F, Arens R, Melief CJ. Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects. Clin Cancer Res. 2013 Oct 1;19(19):5381-9. doi: 10.1158/1078-0432.CCR-12-0781. Epub 2013 Jun 20.
PMID: 23788581
citation: Marabelle A, Kohrt H, Levy R. Intratumoral anti-CTLA-4 therapy: enhancing efficacy while avoiding toxicity. Clin Cancer Res. 2013 Oct 1;19(19):5261-3. doi: 10.1158/1078-0432.CCR-13-1923. Epub 2013 Aug 21.
PMID: 23965900
citation: Robert L, Harview C, Emerson R, Wang X, Mok S, Homet B, Comin-Anduix B, Koya RC, Robins H, Tumeh PC, Ribas A. Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes. Oncoimmunology. 2014 Jun 25;3:e29244. doi: 10.4161/onci.29244. eCollection 2014.
PMID: 25083336
citation: Preusser M, Lim M, Hafler DA, Reardon DA, Sampson JH. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol. 2015 Sep;11(9):504-14. doi: 10.1038/nrneurol.2015.139. Epub 2015 Aug 11.
PMID: 26260659
citation: Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, Durno C, Krueger J, Cabric V, Ramaswamy V, Zhukova N, Mason G, Farah R, Afzal S, Yalon M, Rechavi G, Magimairajan V, Walsh MF, Constantini S, Dvir R, Elhasid R, Reddy A, Osborn M, Sullivan M, Hansford J, Dodgshun A, Klauber-Demore N, Peterson L, Patel S, Lindhorst S, Atkinson J, Cohen Z, Laframboise R, Dirks P, Taylor M, Malkin D, Albrecht S, Dudley RW, Jabado N, Hawkins CE, Shlien A, Tabori U. Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. J Clin Oncol. 2016 Jul 1;34(19):2206-11. doi: 10.1200/JCO.2016.66.6552. Epub 2016 Mar 21.
PMID: 27001570
responsible party type: Principal Investigator
investigator affiliation: Universitair Ziekenhuis Brussel
investigator full name: Bart Neyns
investigator title: Head of Medical Oncology
mesh term: Glioblastoma
mesh term: Nivolumab
mesh term: Ipilimumab
mesh term: Pharmaceutical Solutions
sharing ipd: No