<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/NCT02974621</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2016-01769</org_study_id>
    <secondary_id>NCI-2016-01769</secondary_id>
    <secondary_id>17-735</secondary_id>
    <secondary_id>10067</secondary_id>
    <secondary_id>10067</secondary_id>
    <secondary_id>UM1CA186709</secondary_id>
    <nct_id>NCT02974621</nct_id>
  </id_info>
  <brief_title>Cediranib Maleate and Olaparib Compared to Bevacizumab in Treating Patients With Recurrent Glioblastoma</brief_title>
  <official_title>A Randomized Phase 2 Trial of Cediranib and Olaparib Compared to Bevacizumab in Patients With Recurrent Glioblastoma Who Have Not Received Prior VEGF Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</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 randomized phase II trial studies how well cediranib maleate and olaparib work compared&#xD;
      to bevacizumab in treating patients with glioblastoma that has come back (recurrent).&#xD;
      Cediranib maleate and olaparib may stop the growth of tumor cells by blocking some of the&#xD;
      enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as&#xD;
      bevacizumab, may help the body's immune system attack the cancer, and may interfere with the&#xD;
      ability of tumor cells to grow and spread.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To compare the antitumor activity of cediranib maleate (cediranib)/olaparib versus&#xD;
      reference bevacizumab monotherapy, as measured by progression-free survival at 6 months&#xD;
      (PF6), in patients with recurrent glioblastoma (GBM).&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To compare overall survival (OS), progression free survival (PFS) and objective response&#xD;
      (ORR) in patients with recurrent GBM treated with cediranib/olaparib versus bevacizumab.&#xD;
&#xD;
      II. To assess the safety of the combination of olaparib and cediranib in patients with&#xD;
      recurrent GBM.&#xD;
&#xD;
      III. To evaluate the association of blood based biomarkers involved with angiogenesis using&#xD;
      the Biomarker Review Committee-approved Plasma Angiome Panel (bFGF, Ang-1, Ang-2, Tie-2,&#xD;
      SDF1-alpha, Collagen IV, PlGF, sVEGFR1, sVEGFR2, VEGF, Il-1beta, Il-6, Il-8, TNF-alpha, CAIX)&#xD;
      with the clinical activity of cediranib/olaparib.&#xD;
&#xD;
      IV. To evaluate the association of tissue biomarkers involved with deoxyribonucleic acid&#xD;
      (DNA) repair using the Biomarker Review Committee-approved BROCA panel with the clinical&#xD;
      activity of cediranib/olaparib.&#xD;
&#xD;
      V. To identify genomic alteration by whole exome sequencing in GBM tumor specimens that&#xD;
      correlate with the clinical activity of cediranib/olaparib.&#xD;
&#xD;
      VI. To evaluate the association of magnetic resonance imaging (MRI) imaging parameters (tumor&#xD;
      perfusion and oxygenation, brain tumor cellularity) with the biological response of&#xD;
      cediranib/olaparib.&#xD;
&#xD;
      VII. To contribute genetic analysis data from de-identified biospecimens to Genomic Data&#xD;
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current&#xD;
      and future research; specimens will be annotated with key clinical data, including&#xD;
      presentation, diagnosis, staging, summary treatment, and if possible, outcome.&#xD;
&#xD;
      VIII. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA&#xD;
      analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical&#xD;
      Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 arms.&#xD;
&#xD;
      ARM A: Patients receive olaparib orally (PO) twice daily (BID) and cediranib maleate PO once&#xD;
      daily (QD) on days 1-28.&#xD;
&#xD;
      ARM B: Patients receive bevacizumab intravenously (IV) over 30-90 minutes every 2 weeks.&#xD;
&#xD;
      In both arms, cycles repeat every 28 days in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days and then&#xD;
      periodically for 3 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 7, 2017</start_date>
  <completion_date type="Anticipated">July 20, 2024</completion_date>
  <primary_completion_date type="Actual">December 31, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>Time from randomization to the earlier of progression or death due to any cause, assessed at 6 months</time_frame>
    <description>Defined as the proportion of subjects in the analysis population who remain progression-free for at least 6 months following initiation of study therapy. Will be calculated with the Kaplan-Meier method and the log-rank test will be conducted to compare between the study arms. 95% confidence interval (CI) will be provided for proportion outcomes.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Time from randomization to death due to any cause or censored at date last known alive, assessed up to 3 years</time_frame>
    <description>OS will be calculated with the Kaplan-Meier method and the log-rank test will be conducted to compare between the study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events (AE)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Maximum grade AE during treatment will be reported using 95% binomial confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of circulating cytokines involved with angiogenesis</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular false discovery rate (FDR) (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of serial circulating biomarkers involved with deoxyribonucleic acid (DNA) repair</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor genomic alteration</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be assessed by whole exome sequencing. Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Imaging correlates (vascular permeability, tumor perfusion and oxygenation, brain tumor cellularity)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">70</enrollment>
  <condition>Recurrent Glioblastoma</condition>
  <arm_group>
    <arm_group_label>Arm A (olaparib, cediranib maleate)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive olaparib PO BID and cediranib maleate PO once QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B (bevacizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm B (bevacizumab)</arm_group_label>
    <other_name>ABP 215</other_name>
    <other_name>Anti-VEGF</other_name>
    <other_name>Anti-VEGF Humanized Monoclonal Antibody</other_name>
    <other_name>Anti-VEGF Monoclonal Antibody SIBP04</other_name>
    <other_name>Anti-VEGF rhuMAb</other_name>
    <other_name>Avastin</other_name>
    <other_name>BAT 1706</other_name>
    <other_name>BAT-1706</other_name>
    <other_name>BAT1706</other_name>
    <other_name>BAT1706 Biosimilar</other_name>
    <other_name>Bevacizumab awwb</other_name>
    <other_name>Bevacizumab Biosimilar ABP 215</other_name>
    <other_name>Bevacizumab Biosimilar BAT1706</other_name>
    <other_name>Bevacizumab Biosimilar BEVZ92</other_name>
    <other_name>Bevacizumab Biosimilar BI 695502</other_name>
    <other_name>Bevacizumab Biosimilar CBT 124</other_name>
    <other_name>Bevacizumab Biosimilar CT-P16</other_name>
    <other_name>Bevacizumab Biosimilar FKB238</other_name>
    <other_name>Bevacizumab Biosimilar GB-222</other_name>
    <other_name>Bevacizumab Biosimilar HD204</other_name>
    <other_name>Bevacizumab Biosimilar HLX04</other_name>
    <other_name>Bevacizumab Biosimilar IBI305</other_name>
    <other_name>Bevacizumab Biosimilar LY01008</other_name>
    <other_name>Bevacizumab Biosimilar MIL60</other_name>
    <other_name>Bevacizumab Biosimilar Mvasi</other_name>
    <other_name>Bevacizumab Biosimilar MYL-1402O</other_name>
    <other_name>Bevacizumab Biosimilar QL 1101</other_name>
    <other_name>Bevacizumab Biosimilar QL1101</other_name>
    <other_name>Bevacizumab Biosimilar RPH-001</other_name>
    <other_name>Bevacizumab Biosimilar SCT501</other_name>
    <other_name>Bevacizumab Biosimilar Zirabev</other_name>
    <other_name>Bevacizumab-adcd</other_name>
    <other_name>Bevacizumab-awwb</other_name>
    <other_name>Bevacizumab-bvzr</other_name>
    <other_name>BP102</other_name>
    <other_name>BP102 Biosimilar</other_name>
    <other_name>CT-P16</other_name>
    <other_name>HD204</other_name>
    <other_name>Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer</other_name>
    <other_name>Mvasi</other_name>
    <other_name>MYL-1402O</other_name>
    <other_name>QL1101</other_name>
    <other_name>Recombinant Humanized Anti-VEGF Monoclonal Antibody</other_name>
    <other_name>rhuMab-VEGF</other_name>
    <other_name>SCT501</other_name>
    <other_name>SIBP 04</other_name>
    <other_name>SIBP-04</other_name>
    <other_name>SIBP04</other_name>
    <other_name>Vegzelma</other_name>
    <other_name>Zirabev</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cediranib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm A (olaparib, cediranib maleate)</arm_group_label>
    <other_name>AZ-D2171</other_name>
    <other_name>AZD2171</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cediranib Maleate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm A (olaparib, cediranib maleate)</arm_group_label>
    <other_name>AZD2171</other_name>
    <other_name>AZD2171 Maleate</other_name>
    <other_name>Recentin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Olaparib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm A (olaparib, cediranib maleate)</arm_group_label>
    <other_name>AZD 2281</other_name>
    <other_name>AZD-2281</other_name>
    <other_name>AZD2281</other_name>
    <other_name>KU-0059436</other_name>
    <other_name>Lynparza</other_name>
    <other_name>Olanib</other_name>
    <other_name>Olaparix</other_name>
    <other_name>PARP Inhibitor AZD2281</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Unequivocal evidence of progressive disease on contrast-enhanced brain computed&#xD;
             tomography (CT) or MRI as defined by Response Assessment in Neuro-Oncology (RANO)&#xD;
             criteria, or have documented recurrent glioblastoma on diagnostic biopsy&#xD;
&#xD;
          -  Previous therapy with at least radiotherapy and temozolomide&#xD;
&#xD;
          -  Must be 12 weeks from radiotherapy; if patients are within 12 weeks of radiotherapy,&#xD;
             then the progressive lesion must be outside of the high-dose radiation target volume&#xD;
             or have unequivocal evidence of progressive tumor on a biopsy specimen&#xD;
&#xD;
          -  Only first and second recurrences of GBM are eligible&#xD;
&#xD;
          -  From the projected start of scheduled study treatment, the following time periods must&#xD;
             have elapsed: 5 half-lives from investigational agents, 4 weeks from cytotoxic therapy&#xD;
             (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from&#xD;
             antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other systemic&#xD;
             anti-tumor therapies; treatment on study may start one day after discontinuation of&#xD;
             the optune device&#xD;
&#xD;
          -  All adverse events grade &gt; 1 related to prior therapies (chemotherapy, radiotherapy,&#xD;
             and/or surgery) must be resolved, except for alopecia&#xD;
&#xD;
          -  Willingness to release archival tissue sample for research purposes, if available&#xD;
&#xD;
          -  Karnofsky performance status &gt;= 60&#xD;
&#xD;
          -  Life expectancy of at least 3 months&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Hemoglobin &gt;= 10.0 g/dL and no blood transfusions in the 28 days prior to&#xD;
             entry/randomization&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 2.5 x institutional upper limit of normal&#xD;
&#xD;
          -  Creatinine should not exceed the institutional upper limit of normal OR creatinine&#xD;
             clearance &gt;= 60 mL/min/1.73 m^2&#xD;
&#xD;
          -  Urine protein: creatinine (UPC) ratio &lt; 1 or urine dipstick for proteinuria =&lt; 2+&#xD;
             (note: if the UPC ratio is &gt;= 1.0 then a 24-hour urine collection should be performed&#xD;
             and this must demonstrate =&lt; 1 g of protein in 24 hours)&#xD;
&#xD;
          -  CT or MRI within 14 days prior to start of study drug&#xD;
&#xD;
          -  Corticosteroid dose must be stable or decreasing for at least 5 days prior to the&#xD;
             baseline MRI scan&#xD;
&#xD;
          -  The effects of olaparib and cediranib on the developing human fetus are unknown;&#xD;
             female subjects must either be of non-reproductive potential, not breast-feeding or&#xD;
             must have a negative urine or serum pregnancy test within 28 days of study treatment,&#xD;
             confirmed prior to treatment on day 1; women of child-bearing potential and men must&#xD;
             agree to use adequate contraception (hormonal or barrier method of birth control;&#xD;
             abstinence) prior to study entry and for the duration of study participation; should a&#xD;
             woman become pregnant or suspect she is pregnant while she or her partner is&#xD;
             participating in this study, she should inform her treating physician immediately; men&#xD;
             treated or enrolled on this protocol must also agree to use adequate contraception&#xD;
             prior to the study, for the duration of study participation, and 6 months after&#xD;
             completion of olaparib + cediranib administration&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants should not have received any other investigational agents nor have&#xD;
             participated in an investigational trial within the past 4 weeks&#xD;
&#xD;
          -  Participants may not have had prior use of PARP inhibitors; patients may not have&#xD;
             received prior treatment affecting the VEGF pathway including but not limited to&#xD;
             thalidomide, bevacizumab, sunitinib, or sorafenib&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to olaparib, cediranib or bevacizumab&#xD;
&#xD;
          -  Participants may not have any evidence of ongoing inadequately controlled hypertension&#xD;
             (defined as a systolic blood pressure [BP] of &gt; 140 mmHg or a diastolic BP of &gt; 90&#xD;
             mmHg); patients with hypertension may not be on more than three antihypertensive&#xD;
             medications for management of their blood pressure (medications that combine two&#xD;
             anti-hypertensives into one are considered as two medications); it is strongly&#xD;
             recommended that patients who require three antihypertensive medications for baseline&#xD;
             management of pre-existing hypertension be actively followed by a cardiologist or&#xD;
             blood pressure specialist for management of BP while on protocol&#xD;
&#xD;
          -  Participants may not have had any prior history of hypertensive crisis or hypertensive&#xD;
             encephalopathy&#xD;
&#xD;
          -  Participants may not have had history of abdominal fistula or gastrointestinal&#xD;
             perforation within the past 6 months&#xD;
&#xD;
          -  Participants may not have had a history of intra-abdominal abscess within the past 6&#xD;
             months&#xD;
&#xD;
          -  Patients may not have a known or confirmed history of pneumonitis&#xD;
&#xD;
          -  Participants may not have current signs and/or symptoms of bowel obstruction or signs&#xD;
             and/or symptoms of bowel obstruction within 3 months prior to starting study drugs&#xD;
&#xD;
          -  Participants may not have a dependency on IV hydration or total parenteral nutrition&#xD;
             (TPN)&#xD;
&#xD;
          -  Patients with myelodysplastic syndrome/acute myeloid leukemia&#xD;
&#xD;
          -  Participants with any concomitant or prior invasive malignancies are ineligible with&#xD;
             the following exceptions:&#xD;
&#xD;
               -  Treated limited-stage basal cell or squamous cell carcinoma of the skin&#xD;
&#xD;
               -  Carcinoma in situ of the breast or cervix&#xD;
&#xD;
               -  Prior cancer treated with curative intent with no evidence of recurrent disease 3&#xD;
                  years following diagnosis and judged by the investigator to be at low risk of&#xD;
                  recurrence&#xD;
&#xD;
          -  Participants with any of the following:&#xD;
&#xD;
               -  History of myocardial infarction within six months&#xD;
&#xD;
               -  Unstable angina&#xD;
&#xD;
               -  History of cerebrovascular accident (CVA) within 6 months&#xD;
&#xD;
               -  New York Heart Association grade II or greater congestive heart failure&#xD;
&#xD;
               -  Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)&#xD;
&#xD;
               -  Clinically significant peripheral vascular disease&#xD;
&#xD;
          -  If cardiac function assessment is clinically indicated or performed: participants will&#xD;
             be ineligible if left ventricular ejection fraction (LVEF) is less than normal per&#xD;
             institutional guidelines, or &lt; 55%, if the threshold for normal is not otherwise&#xD;
             specified by institutional guidelines&#xD;
&#xD;
          -  Participants may not have corrected QT (QTc) &gt; 470 msec or family history of long QT&#xD;
             syndrome&#xD;
&#xD;
          -  Participants may not have a major surgical procedure, open biopsy, or significant&#xD;
             traumatic injury within 28 days prior to starting cediranib; anticipation of need for&#xD;
             major surgical procedures during the course of the study also excludes patients from&#xD;
             the trial&#xD;
&#xD;
          -  Participants should not have any uncontrolled intercurrent illness including, but&#xD;
             limited to ongoing or active infection, symptomatic congestive heart failure, unstable&#xD;
             angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that&#xD;
             would limit compliance with study requirements&#xD;
&#xD;
          -  Participants receiving any medications or substances that are strong inhibitors or&#xD;
             inducers of CYP3A4 or moderate inhibitors of CYP3A4 are ineligible; the study team&#xD;
             should check a frequently-updated medical reference for a list of drugs to avoid or&#xD;
             minimize use of; as part of the enrollment/informed consent procedures, the patient&#xD;
             will be counseled on the risk of interactions with other agents, and what to do if new&#xD;
             medications need to be prescribed or if the patient is considering a new&#xD;
             over-the-counter medicine or herbal product; dihydropyridine calcium-channel blockers&#xD;
             are permitted for management of hypertension; patient drug information handout and&#xD;
             wallet card should be provided to patients&#xD;
&#xD;
          -  Pregnant women are excluded from this study because cediranib and olaparib agent with&#xD;
             the potential for teratogenic or abortifacient effects; because there is an unknown&#xD;
             but potential risk for adverse events in nursing infants secondary to treatment of the&#xD;
             mother with cediranib and olaparib breastfeeding should be discontinued if the mother&#xD;
             is treated with cediranib and olaparib; these potential risks may also apply to other&#xD;
             agents used in this study&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             cediranib and olaparib; in addition, these patients are at increased risk of lethal&#xD;
             infections when treated with marrow-suppressive therapy; appropriate studies will be&#xD;
             undertaken in patients receiving combination antiretroviral therapy when indicated&#xD;
&#xD;
          -  Current use of a prohibited medication; the following medications or non-drug&#xD;
             therapies are prohibited:&#xD;
&#xD;
               -  Other anti-cancer therapy while on study treatment&#xD;
&#xD;
               -  Concurrent treatment with bisphosphonates is permitted; however, treatment must&#xD;
                  be initiated prior to the first dose of study therapy; prophylactic use of&#xD;
                  bisphosphonates in patients without bone disease is not permitted, except for the&#xD;
                  treatment of osteoporosis&#xD;
&#xD;
               -  Because the composition, pharmacokinetics (PK), and metabolism of many herbal&#xD;
                  supplements are unknown; the concurrent use of all herbal supplements is&#xD;
                  prohibited during the study (including, but not limited to, cannabis, S. John's&#xD;
                  wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA],&#xD;
                  yohimbe, saw palmetto or ginseng)&#xD;
&#xD;
               -  Raloxifene is allowed for patients taking it for bone health&#xD;
&#xD;
          -  Participants should not have evidence of coagulopathy or bleeding diathesis;&#xD;
             therapeutic anticoagulation for prior thromboembolic events is permitted&#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>Isabel Arrillaga-Romany</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber - Harvard Cancer Center LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UC San Diego Moores Cancer Center</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCHealth University of Colorado Hospital</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital-Derby Care Center</name>
      <address>
        <city>Derby</city>
        <state>Connecticut</state>
        <zip>06418</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital Care Center-Fairfield</name>
      <address>
        <city>Fairfield</city>
        <state>Connecticut</state>
        <zip>06824</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital Care Center - Guilford</name>
      <address>
        <city>Guilford</city>
        <state>Connecticut</state>
        <zip>06437</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital Care Center at Saint Francis</name>
      <address>
        <city>Hartford</city>
        <state>Connecticut</state>
        <zip>06105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Center/Yale-New Haven Hospital</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital-Orange Care Center</name>
      <address>
        <city>Orange</city>
        <state>Connecticut</state>
        <zip>06477</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital-Torrington Care Center</name>
      <address>
        <city>Torrington</city>
        <state>Connecticut</state>
        <zip>06790</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital Care Center-Trumbull</name>
      <address>
        <city>Trumbull</city>
        <state>Connecticut</state>
        <zip>06611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital-Waterbury Care Center</name>
      <address>
        <city>Waterbury</city>
        <state>Connecticut</state>
        <zip>06708</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Hospital Care Center - Waterford</name>
      <address>
        <city>Waterford</city>
        <state>Connecticut</state>
        <zip>06385</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kentucky/Markey Cancer Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital Cancer Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</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>
    <facility>
      <name>Siteman Cancer Center at West County Hospital</name>
      <address>
        <city>Creve Coeur</city>
        <state>Missouri</state>
        <zip>63141</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siteman Cancer Center-South County</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63129</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siteman Cancer Center at Christian Hospital</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siteman Cancer Center at Saint Peters Hospital</name>
      <address>
        <city>Saint Peters</city>
        <state>Missouri</state>
        <zip>63376</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Cancer Institute (UPCI)</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>November 23, 2016</study_first_submitted>
  <study_first_submitted_qc>November 23, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2016</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Antineoplastic Agents, Immunological</mesh_term>
    <mesh_term>Olaparib</mesh_term>
    <mesh_term>Cediranib</mesh_term>
    <mesh_term>Endothelial Growth Factors</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
    <mesh_term>Immunoglobulin G</mesh_term>
    <mesh_term>Maleic acid</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02974621
org study id: NCI-2016-01769
secondary id: NCI-2016-01769
secondary id: 17-735
secondary id: 10067
secondary id: 10067
secondary id: UM1CA186709
nct id: NCT02974621
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This randomized phase II trial studies how well cediranib maleate and olaparib work compared
      to bevacizumab in treating patients with glioblastoma that has come back (recurrent).
      Cediranib maleate and olaparib may stop the growth of tumor cells by blocking some of the
      enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as
      bevacizumab, may help the body's immune system attack the cancer, and may interfere with the
      ability of tumor cells to grow and spread.
PRIMARY OBJECTIVES:

      I. To compare the antitumor activity of cediranib maleate (cediranib)/olaparib versus
      reference bevacizumab monotherapy, as measured by progression-free survival at 6 months
      (PF6), in patients with recurrent glioblastoma (GBM).

      SECONDARY OBJECTIVES:

      I. To compare overall survival (OS), progression free survival (PFS) and objective response
      (ORR) in patients with recurrent GBM treated with cediranib/olaparib versus bevacizumab.

      II. To assess the safety of the combination of olaparib and cediranib in patients with
      recurrent GBM.

      III. To evaluate the association of blood based biomarkers involved with angiogenesis using
      the Biomarker Review Committee-approved Plasma Angiome Panel (bFGF, Ang-1, Ang-2, Tie-2,
      SDF1-alpha, Collagen IV, PlGF, sVEGFR1, sVEGFR2, VEGF, Il-1beta, Il-6, Il-8, TNF-alpha, CAIX)
      with the clinical activity of cediranib/olaparib.

      IV. To evaluate the association of tissue biomarkers involved with deoxyribonucleic acid
      (DNA) repair using the Biomarker Review Committee-approved BROCA panel with the clinical
      activity of cediranib/olaparib.

      V. To identify genomic alteration by whole exome sequencing in GBM tumor specimens that
      correlate with the clinical activity of cediranib/olaparib.

      VI. To evaluate the association of magnetic resonance imaging (MRI) imaging parameters (tumor
      perfusion and oxygenation, brain tumor cellularity) with the biological response of
      cediranib/olaparib.

      VII. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
      and future research; specimens will be annotated with key clinical data, including
      presentation, diagnosis, staging, summary treatment, and if possible, outcome.

      VIII. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
      analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
      Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive olaparib orally (PO) twice daily (BID) and cediranib maleate PO once
      daily (QD) on days 1-28.

      ARM B: Patients receive bevacizumab intravenously (IV) over 30-90 minutes every 2 weeks.

      In both arms, cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then
      periodically for 3 years.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free survival
time frame: Time from randomization to the earlier of progression or death due to any cause, assessed at 6 months
description: Defined as the proportion of subjects in the analysis population who remain progression-free for at least 6 months following initiation of study therapy. Will be calculated with the Kaplan-Meier method and the log-rank test will be conducted to compare between the study arms. 95% confidence interval (CI) will be provided for proportion outcomes.
measure: Overall survival (OS)
time frame: Time from randomization to death due to any cause or censored at date last known alive, assessed up to 3 years
description: OS will be calculated with the Kaplan-Meier method and the log-rank test will be conducted to compare between the study arms.
measure: Incidence of adverse events (AE)
time frame: Up to 3 years
description: Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Maximum grade AE during treatment will be reported using 95% binomial confidence intervals.
measure: Levels of circulating cytokines involved with angiogenesis
time frame: Up to 3 years
description: Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular false discovery rate (FDR) (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.
measure: Levels of serial circulating biomarkers involved with deoxyribonucleic acid (DNA) repair
time frame: Up to 3 years
description: Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.
measure: Tumor genomic alteration
time frame: Up to 3 years
description: Will be assessed by whole exome sequencing. Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.
measure: Imaging correlates (vascular permeability, tumor perfusion and oxygenation, brain tumor cellularity)
time frame: Up to 3 years
description: Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.
arm group label: Arm A (olaparib, cediranib maleate)
arm group type: Experimental
description: Patients receive olaparib PO BID and cediranib maleate PO once QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
arm group label: Arm B (bevacizumab)
arm group type: Experimental
description: Patients receive bevacizumab IV over 30-90 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
intervention type: Biological
intervention name: Bevacizumab
description: Given IV
arm group label: Arm B (bevacizumab)
other name: ABP 215
other name: Anti-VEGF
other name: Anti-VEGF Humanized Monoclonal Antibody
other name: Anti-VEGF Monoclonal Antibody SIBP04
other name: Anti-VEGF rhuMAb
other name: Avastin
other name: BAT 1706
other name: BAT-1706
other name: BAT1706
other name: BAT1706 Biosimilar
other name: Bevacizumab awwb
other name: Bevacizumab Biosimilar ABP 215
other name: Bevacizumab Biosimilar BAT1706
other name: Bevacizumab Biosimilar BEVZ92
other name: Bevacizumab Biosimilar BI 695502
other name: Bevacizumab Biosimilar CBT 124
other name: Bevacizumab Biosimilar CT-P16
other name: Bevacizumab Biosimilar FKB238
other name: Bevacizumab Biosimilar GB-222
other name: Bevacizumab Biosimilar HD204
other name: Bevacizumab Biosimilar HLX04
other name: Bevacizumab Biosimilar IBI305
other name: Bevacizumab Biosimilar LY01008
other name: Bevacizumab Biosimilar MIL60
other name: Bevacizumab Biosimilar Mvasi
other name: Bevacizumab Biosimilar MYL-1402O
other name: Bevacizumab Biosimilar QL 1101
other name: Bevacizumab Biosimilar QL1101
other name: Bevacizumab Biosimilar RPH-001
other name: Bevacizumab Biosimilar SCT501
other name: Bevacizumab Biosimilar Zirabev
other name: Bevacizumab-adcd
other name: Bevacizumab-awwb
other name: Bevacizumab-bvzr
other name: BP102
other name: BP102 Biosimilar
other name: CT-P16
other name: HD204
other name: Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
other name: Mvasi
other name: MYL-1402O
other name: QL1101
other name: Recombinant Humanized Anti-VEGF Monoclonal Antibody
other name: rhuMab-VEGF
other name: SCT501
other name: SIBP 04
other name: SIBP-04
other name: SIBP04
other name: Vegzelma
other name: Zirabev
intervention type: Drug
intervention name: Cediranib
description: Given PO
arm group label: Arm A (olaparib, cediranib maleate)
other name: AZ-D2171
other name: AZD2171
intervention type: Drug
intervention name: Cediranib Maleate
description: Given PO
arm group label: Arm A (olaparib, cediranib maleate)
other name: AZD2171
other name: AZD2171 Maleate
other name: Recentin
intervention type: Drug
intervention name: Olaparib
description: Given PO
arm group label: Arm A (olaparib, cediranib maleate)
other name: AZD 2281
other name: AZD-2281
other name: AZD2281
other name: KU-0059436
other name: Lynparza
other name: Olanib
other name: Olaparix
other name: PARP Inhibitor AZD2281
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Isabel Arrillaga-Romany
role: Principal Investigator
affiliation: Dana-Farber - Harvard Cancer Center LAO
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country: United States
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Recurrence
mesh term: Bevacizumab
mesh term: Antineoplastic Agents, Immunological
mesh term: Olaparib
mesh term: Cediranib
mesh term: Endothelial Growth Factors
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal
mesh term: Immunoglobulin G
mesh term: Maleic acid