xml: <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/NCT06006013</url>
    </required_header>
    <id_info>
      <org_study_id>STUDY00005532</org_study_id>
      <secondary_id>NCI-2023-04952</secondary_id>
      <secondary_id>STUDY00005532</secondary_id>
      <secondary_id>WINSHIP5823-22</secondary_id>
      <secondary_id>P30CA138292</secondary_id>
      <nct_id>NCT06006013</nct_id>
    </id_info>
    <brief_title>Cabozantinib in Combination With Atezolizumab for the Treatment of Patients With Locally Advanced, Metastatic, or Unresectable Adrenal Cortical Cancer</brief_title>
    <official_title>Phase II Open Label, Single-Arm Study of Cabozantinib in Combination With Atezolizumab in the Treatment of Locally Advanced or Metastatic Adrenocortical Carcinoma</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Emory University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>National Cancer Institute (NCI)</agency>
        <agency_class>NIH</agency_class>
      </collaborator>
    </sponsors>
    <source>Emory University</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>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This phase II trial tests how well cabozantinib in combination with atezolizumab works in&#xD;
        treating patients with adrenal cortical cancer that has spread to nearby tissue or lymph&#xD;
        nodes (locally advanced), that has spread from where it first started (primary site) to other&#xD;
        places in the body (metastatic), or that cannot be removed by surgery (unresectable).&#xD;
        Cabozantinib inhibits receptor tyrosine kinases, which are receptors commonly over-expressed&#xD;
        by tumor cells. This may result in an inhibition of both tumor growth and blood vessel&#xD;
        formation, eventually leading to a decrease in tumor size or extent in the body.&#xD;
        Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune&#xD;
        system attack the cancer, and may interfere with the ability of tumor cells to grow and&#xD;
        spread. Adding cabozantinib to atezolizumab may be more effective at treating patients with&#xD;
        adrenal cortical cancer than giving these drugs alone.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        PRIMARY OBJECTIVE:&#xD;
  &#xD;
        I. To evaluate the anti-tumor activity of the combination of cabozantinib S-malate&#xD;
        (cabozantinib) and atezolizumab by assessing the overall response rate (ORR) as measured by&#xD;
        Response Evaluation Criteria in Solid Tumors (RECIST 1.1.).&#xD;
  &#xD;
        SECONDARY OBJECTIVE:&#xD;
  &#xD;
        I. To evaluate the efficacy of the combination of cabozantinib and atezolizumab as measured&#xD;
        by progression free survival and overall survival assessed up to 2 years, safety and&#xD;
        tolerability of the combination.&#xD;
  &#xD;
        TERTIARY/EXPLORATORY OBJECTIVE:&#xD;
  &#xD;
        I. To assess tissue-based assays in archival tissue and correlative changes in peripheral&#xD;
        T-cell subsets, myeloid derived suppressor cells (MDSC), blood inflammatory markers and&#xD;
        cytokines.&#xD;
  &#xD;
        OUTLINE:&#xD;
  &#xD;
        Patients receive cabozantinib orally (PO) once daily (QD) on days 1-21 of each cycle and&#xD;
        atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat&#xD;
        every 21 days in the absence of disease progression or unacceptable toxicity. Patients also&#xD;
        undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) at screening and&#xD;
        then every 12 weeks on study and undergo collection of blood samples at screening, on study,&#xD;
        and at end of treatment. Patients without archival tissue also undergo biopsy at screening.&#xD;
  &#xD;
        After completion of study treatment, patients are followed for 28 days and then up to 2 years&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">December 16, 2025</completion_date>
    <primary_completion_date type="Anticipated">December 16, 2025</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <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>Overall response rate (ORR)</measure>
      <time_frame>Every 12 weeks, assessed up to 2 years</time_frame>
      <description>ORR is defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors version 1.1. ORR will be estimated by the Clopper-Pearson method with 95% confidence intervals. Descriptive statistics on continuous data will include means, medians, standard deviations, and ranges, while categorical data will be summarized using frequency counts and percentages. Will explore whether the sample size can inform on the association between ORR and demographics or molecular biomarkers by Fisher's exact test (categorical variables) and Wilcoxon rank-sum test (continuous variables) wherever appropriate (this analysis is exploratory in nature).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Progression free survival</measure>
      <time_frame>From treatment initiation until disease progression, death due to disease, or lost to follow up, assessed up to 2 years</time_frame>
      <description>The Kaplan-Meier method will be used to estimate median event time (with 95% confidence interval).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall survival</measure>
      <time_frame>From treatment initiation until death due to any cause or loss to follow up, assessed up to 2 years</time_frame>
      <description>The Kaplan-Meier method will be used to estimate median event time (with 95% confidence interval).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of adverse events</measure>
      <time_frame>Up to 2 years</time_frame>
      <description>Evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Safety endpoints will be tabulated using frequency such as percent with at least one adverse event, percent for each grade, and percent with grade 3 or more adverse events.</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">21</enrollment>
    <condition>Locally Advanced Adrenal Cortical Carcinoma</condition>
    <condition>Metastatic Adrenal Cortical Carcinoma</condition>
    <condition>Stage III Adrenal Cortical Carcinoma AJCC v8</condition>
    <condition>Stage IV Adrenal Cortical Carcinoma AJCC v8</condition>
    <condition>Unresectable Adrenal Cortical Carcinoma</condition>
    <arm_group>
      <arm_group_label>Treatment (cabozantinib, atezolizumab)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients receive cabozantinib PO QD on days 1-21 of each cycle and atezolizumab IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI at screening and then every 12 weeks on study and undergo collection of blood samples at screening, on study, and at end of treatment. Patients without archival tissue also undergo biopsy at screening.</description>
    </arm_group>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Atezolizumab</intervention_name>
      <description>Given IV</description>
      <arm_group_label>Treatment (cabozantinib, atezolizumab)</arm_group_label>
      <other_name>MPDL 3280A</other_name>
      <other_name>MPDL 328OA</other_name>
      <other_name>MPDL-3280A</other_name>
      <other_name>MPDL3280A</other_name>
      <other_name>MPDL328OA</other_name>
      <other_name>RG7446</other_name>
      <other_name>RO5541267</other_name>
      <other_name>Tecentriq</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Biopsy</intervention_name>
      <description>Undergo biopsy</description>
      <arm_group_label>Treatment (cabozantinib, atezolizumab)</arm_group_label>
      <other_name>BIOPSY_TYPE</other_name>
      <other_name>Bx</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Biospecimen Collection</intervention_name>
      <description>Undergo collection of blood samples</description>
      <arm_group_label>Treatment (cabozantinib, atezolizumab)</arm_group_label>
      <other_name>Biological Sample Collection</other_name>
      <other_name>Biospecimen Collected</other_name>
      <other_name>Specimen Collection</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Cabozantinib S-malate</intervention_name>
      <description>Given PO</description>
      <arm_group_label>Treatment (cabozantinib, atezolizumab)</arm_group_label>
      <other_name>BMS-907351</other_name>
      <other_name>Cabometyx</other_name>
      <other_name>Cometriq</other_name>
      <other_name>XL-184</other_name>
      <other_name>XL184</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Computed Tomography</intervention_name>
      <description>Undergo CT</description>
      <arm_group_label>Treatment (cabozantinib, atezolizumab)</arm_group_label>
      <other_name>CAT</other_name>
      <other_name>CAT Scan</other_name>
      <other_name>Computed Axial Tomography</other_name>
      <other_name>Computerized Axial Tomography</other_name>
      <other_name>Computerized axial tomography (procedure)</other_name>
      <other_name>Computerized Tomography</other_name>
      <other_name>CT</other_name>
      <other_name>CT Scan</other_name>
      <other_name>tomography</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Magnetic Resonance Imaging</intervention_name>
      <description>Undergo MRI</description>
      <arm_group_label>Treatment (cabozantinib, atezolizumab)</arm_group_label>
      <other_name>Magnetic Resonance</other_name>
      <other_name>Magnetic resonance imaging (procedure)</other_name>
      <other_name>Magnetic Resonance Imaging Scan</other_name>
      <other_name>Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance</other_name>
      <other_name>MR</other_name>
      <other_name>MR Imaging</other_name>
      <other_name>MRI</other_name>
      <other_name>MRI Scan</other_name>
      <other_name>NMR Imaging</other_name>
      <other_name>NMRI</other_name>
      <other_name>Nuclear Magnetic Resonance Imaging</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Male or female&#xD;
  &#xD;
            -  Age &gt;= 18 years&#xD;
  &#xD;
            -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 50%)&#xD;
  &#xD;
            -  Metastatic disease or unresectable locally advanced disease&#xD;
  &#xD;
            -  Histologically documented adrenal cortical carcinoma&#xD;
  &#xD;
            -  Untreated or having received any number of lines of prior therapy&#xD;
  &#xD;
            -  Measurable disease per RECIST version (v)1.1&#xD;
  &#xD;
            -  Life expectancy &gt;= 12 weeks&#xD;
  &#xD;
            -  Tumor tissue samples must be available for submission prior to initiation of study&#xD;
               treatment. If not, agree to undergo biopsy&#xD;
  &#xD;
            -  Recovery to baseline or =&lt; grade 1 Common Terminology Criteria for Adverse Events&#xD;
               (CTCAE) v5 from toxicities related to any prior treatments, unless adverse event&#xD;
               (AE)(s) are clinically nonsignificant and/or stable on supportive therapy&#xD;
  &#xD;
            -  Absolute neutrophil count (ANC) &gt;= 1500/uL without granulocyte colony-stimulating&#xD;
               factor support (within 28 days before first dose of study treatment)&#xD;
  &#xD;
            -  Lymphocyte count 0.5 x 10^9/L (500/mL) (within 28 days before first dose of study&#xD;
               treatment)&#xD;
  &#xD;
            -  White blood cell count &gt;= 2500/uL (within 28 days before first dose of study&#xD;
               treatment)&#xD;
  &#xD;
            -  Platelets &gt;= 100,000/uL without transfusion (within 28 days before first dose of study&#xD;
               treatment)&#xD;
  &#xD;
            -  Hemoglobin &gt;= 9 g/dL (&gt;= 90 g/L). Patients may be transfused to meet this criterion&#xD;
               (within 28 days before first dose of study treatment)&#xD;
  &#xD;
            -  Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline&#xD;
               phosphatase (ALP) =&lt; 3 x upper limit of normal (ULN). ALP =&lt; 5 x ULN with documented&#xD;
               bone metastases (within 28 days before first dose of study treatment)&#xD;
  &#xD;
            -  Total bilirubin =&lt; 1.5 x ULN (for subjects with Gilbert's disease =&lt; 3 x ULN) (within&#xD;
               28 days before first dose of study treatment)&#xD;
  &#xD;
            -  Serum albumin &gt;= 2.8 g/dl (within 28 days before first dose of study treatment)&#xD;
  &#xD;
            -  Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin&#xD;
               time (PTT) test &lt; 1.3 x the laboratory ULN (within 28 days before first dose of study&#xD;
               treatment)&#xD;
  &#xD;
            -  Serum creatinine =&lt; 1.5 x ULN or calculated creatinine clearance &gt;= 40mL/min (&gt;=&#xD;
               0.675mL/sec) using the Cockcroft-Gault equation (within 28 days before first dose of&#xD;
               study treatment)&#xD;
  &#xD;
            -  Urine protein/creatinine ratio (UPCR) =&lt; 1 mg/mg (=&lt; 113.2 mg/mmol), or 24-h urine&#xD;
               protein =&lt; 1 g (within 28 days before first dose of study treatment)&#xD;
  &#xD;
            -  Negative human immunodeficiency virus (HIV) test at screening, with the following&#xD;
               exception: patients with a positive HIV test at screening are eligible provided they&#xD;
               are stable on anti-retroviral therapy, have a CD4 count &gt;= 200/uL, and have an&#xD;
               undetectable viral load&#xD;
  &#xD;
            -  Negative hepatitis B surface antigen (HBsAg) test at screening&#xD;
  &#xD;
            -  Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody&#xD;
               test followed by a negative HCV ribonucleic acid (RNA) test at screening&#xD;
  &#xD;
                 -  The HCV RNA test must be performed for patients who have a positive HCV antibody&#xD;
                    test&#xD;
  &#xD;
            -  The effects of study drugs on the developing human fetus are unknown. For this reason,&#xD;
               female of child-bearing potential (FCBP) must have a negative serum or urine pregnancy&#xD;
               test prior to starting therapy&#xD;
  &#xD;
            -  FCBP and men treated or enrolled on this protocol must agree to use adequate&#xD;
               contraception with a failure rate &lt; 1% prior to study entry, for the duration of study&#xD;
               participation, and 5 months after completion of study drug administration.&#xD;
  &#xD;
                 -  Examples of contraceptive methods with a failure rate of &lt; 1% per year include&#xD;
                    bilateral tubal ligation, male sterilization, hormonal contraceptives that&#xD;
                    inhibit ovulation, hormone-releasing intrauterine devices, and copper&#xD;
                    intrauterine devices&#xD;
  &#xD;
                 -  The reliability of sexual abstinence should be evaluated in relation to the&#xD;
                    duration of the clinical trial and the preferred and usual lifestyle of the&#xD;
                    patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or&#xD;
                    postovulation methods) and withdrawal are not adequate methods of contraception&#xD;
  &#xD;
                 -  Should a woman become pregnant or suspect she is pregnant while she or her&#xD;
                    partner is participating in this study, she should inform her treating physician&#xD;
                    immediately&#xD;
  &#xD;
            -  Female subjects of childbearing potential must not be pregnant at screening. Female&#xD;
               subjects are considered to be of childbearing potential unless one of the following&#xD;
               criteria is met: documented permanent sterilization (hysterectomy, bilateral&#xD;
               salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined&#xD;
               as 12 months of amenorrhea in a woman &gt; 45 years-of-age in the absence of other&#xD;
               biological or physiological causes. In addition, females &lt; 55 years-of-age must have a&#xD;
               serum follicle stimulating [FSH] level &gt; 40 mIU/mL to confirm menopause). Note:&#xD;
               Documentation may include review of medical records, medical examinations, or medical&#xD;
               history interview by study site&#xD;
  &#xD;
            -  Willingness and ability of the subject to comply with scheduled visits, drug&#xD;
               administration plan, protocol-specified laboratory tests, other study procedures, and&#xD;
               study restrictions&#xD;
  &#xD;
            -  Evidence of a personally signed informed consent indicating that the subject is aware&#xD;
               of the neoplastic nature of the disease and has been informed of the procedures to be&#xD;
               followed, the experimental nature of the therapy, alternatives, potential risks and&#xD;
               discomforts, potential benefits, and other pertinent aspects of study participation&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Receipt of any type of small molecule kinase inhibitor (including investigational&#xD;
               kinase inhibitor) within 2 weeks before first dose of study treatment&#xD;
  &#xD;
            -  Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including&#xD;
               anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies&#xD;
  &#xD;
            -  Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy&#xD;
               (including immunostimulatory agents or investigational agents) within 4 weeks or 5&#xD;
               half-lives of the drug (whichever is longer) before first dose of study treatment&#xD;
  &#xD;
            -  Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy&#xD;
               within 4 weeks before first dose of study treatment. Systemic treatment with&#xD;
               radionuclides within 6 weeks before first dose of study treatment. Subjects with&#xD;
               clinically relevant ongoing complications from prior radiation therapy are not&#xD;
               eligible&#xD;
  &#xD;
            -  Known brain metastases or cranial epidural disease unless adequately treated with&#xD;
               radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks&#xD;
               prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to&#xD;
               first dose of study treatment after major surgery (e.g., removal or biopsy of brain&#xD;
               metastasis). Subjects with known brain metastases or cranial epidural disease should&#xD;
               also have no history of intracranial hemorrhage or spinal hemorrhage. Subjects must&#xD;
               have complete wound healing from major surgery or minor surgery before first dose of&#xD;
               study treatment. Eligible subjects must be neurologically asymptomatic and without&#xD;
               corticosteroid treatment at the time of first dose of study treatment. If subject is&#xD;
               receiving anti-convulsant therapy, the dose is considered stable&#xD;
  &#xD;
            -  Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin&#xD;
               inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet&#xD;
               inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:&#xD;
  &#xD;
                 -  Prophylactic use of low-dose aspirin for cardio-protection (per local applicable&#xD;
                    guidelines) and low-dose low molecular weight heparins (LMWH)&#xD;
  &#xD;
                 -  Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors&#xD;
                    rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who&#xD;
                    are on a stable dose of the anticoagulant for at least 1 week before first dose&#xD;
                    of study treatment without clinically significant hemorrhagic complications from&#xD;
                    the anticoagulation regimen or the tumor&#xD;
  &#xD;
            -  Administration of a live, attenuated vaccine within 30 days before first dose of study&#xD;
               treatment or anticipation of need for such a vaccine during atezolizumab treatment or&#xD;
               within 5 months after the final dose of atezolizumab&#xD;
  &#xD;
            -  Concomitant mitotane use&#xD;
  &#xD;
                 -  Mitotane must have been discontinued 28 days prior to first dose of study&#xD;
                    treatment, with mitotane serum level &lt; 2 mg/L if mitotane administered within&#xD;
                    last 6 months&#xD;
  &#xD;
            -  The subject has uncontrolled, significant intercurrent or recent illness including,&#xD;
               but not limited to, the following conditions:&#xD;
  &#xD;
                 -  Cardiovascular disorders:&#xD;
  &#xD;
                      -  Congestive heart failure New York Heart Association class 3 or 4, unstable&#xD;
                         angina pectoris, serious cardiac arrhythmias&#xD;
  &#xD;
                      -  Uncontrolled hypertension defined as sustained blood pressure (BP) &gt; 140 mm&#xD;
                         Hg systolic or &gt; 90 mm Hg diastolic despite optimal antihypertensive&#xD;
                         treatment&#xD;
  &#xD;
                      -  Stroke (including transient ischemic attack [TIA]), myocardial infarction&#xD;
                         (MI), or other ischemic event, or thromboembolic event (e.g., deep venous&#xD;
                         thrombosis, pulmonary embolism) within 6 months before first dose of study&#xD;
                         treatment&#xD;
  &#xD;
                           -  Subjects with a diagnosis of incidental, subsegmental pulmonary&#xD;
                              embolism (PE) or deep vein thrombosis (DVT) within 6 months are allowed&#xD;
                              if stable, asymptomatic, and treated with a stable dose of permitted&#xD;
                              anticoagulation (see exclusion criterion #6) for at least 1 week before&#xD;
                              first dose of study treatment&#xD;
  &#xD;
                 -  Gastrointestinal (GI) disorders including those associated with a high risk of&#xD;
                    perforation or fistula formation:&#xD;
  &#xD;
                      -  The subject has evidence of tumor invading the GI tract, active peptic ulcer&#xD;
                         disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,&#xD;
                         cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis,&#xD;
                         acute obstruction of the pancreatic duct or common bile duct, or gastric&#xD;
                         outlet obstruction&#xD;
  &#xD;
                      -  Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal&#xD;
                         abscess within 6 months before first dose of study treatment. Note: Complete&#xD;
                         healing of an intra-abdominal abscess must be confirmed before first dose of&#xD;
                         study treatment&#xD;
  &#xD;
                 -  Uncontrolled tumor-related pain:&#xD;
  &#xD;
                      -  Patients requiring pain medication must be on a stable regimen at study&#xD;
                         entry&#xD;
  &#xD;
                      -  Symptomatic lesions (e.g., bone metastases or metastases causing nerve&#xD;
                         impingement) amenable to palliative radiotherapy should be treated prior to&#xD;
                         enrollment. Patients should be recovered from the effects of radiation (see&#xD;
                         exclusion criteria #4 for minimal required duration prior to trial&#xD;
                         enrollment)&#xD;
  &#xD;
                      -  Asymptomatic metastatic lesions that would likely cause functional deficits&#xD;
                         or intractable pain with further growth (e.g., epidural metastasis that is&#xD;
                         not currently associated with spinal cord compression) should be considered&#xD;
                         for loco-regional therapy if appropriate prior to enrollment&#xD;
  &#xD;
                 -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring&#xD;
                    recurrent drainage procedures (once monthly or more frequently)&#xD;
  &#xD;
                      -  Patients with indwelling catheters (e.g., PleurX) are allowed&#xD;
  &#xD;
                 -  Uncontrolled or symptomatic hypercalcemia (ionized calcium &gt; 1.5 mmol/L, calcium&#xD;
                    &gt; 12 mg/dL or corrected serum calcium &gt; ULN)&#xD;
  &#xD;
                 -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,&#xD;
                    bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis,&#xD;
                    or evidence of active pneumonitis on screening chest computed tomography (CT)&#xD;
                    scan&#xD;
  &#xD;
                      -  History of radiation pneumonitis in the radiation field (fibrosis) is&#xD;
                         permitted&#xD;
  &#xD;
            -  Clinically significant hematuria, hematemesis, or hemoptysis of &gt; 0.5 teaspoon (2.5&#xD;
               ml) of red blood, or other history of significant bleeding (e.g., pulmonary&#xD;
               hemorrhage) within 12 weeks before first dose of study treatment&#xD;
  &#xD;
            -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease&#xD;
               manifestation&#xD;
  &#xD;
            -  Lesions invading or encasing any major blood vessels&#xD;
  &#xD;
            -  Other clinically significant disorders that would preclude safe study participation.&#xD;
  &#xD;
                 -  Active or history of autoimmune disease or immune deficiency, including, but not&#xD;
                    limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus&#xD;
                    erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid&#xD;
                    antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barré&#xD;
                    syndrome, or multiple sclerosis with the following exceptions:&#xD;
  &#xD;
                      -  Type 1 diabetes mellitus on an insulin regimen&#xD;
  &#xD;
                      -  Hypothyroidism only requiring hormone replacement&#xD;
  &#xD;
                      -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with&#xD;
                         dermatologic manifestations only (e.g., patients with psoriatic arthritis&#xD;
                         are excluded) are eligible for the study provided all of following&#xD;
                         conditions are met:&#xD;
  &#xD;
                           -  Rash must cover &lt; 10% of body surface area&#xD;
  &#xD;
                           -  Disease is well controlled at baseline and requires only low-potency&#xD;
                              topical corticosteroids&#xD;
  &#xD;
                           -  No occurrence of acute exacerbations of the underlying condition&#xD;
                              requiring psoralen plus ultraviolet A radiation, methotrexate,&#xD;
                              retinoids, biologic agents, oral calcineurin inhibitors, or&#xD;
                              high-potency or oral corticosteroids within the previous 12 months&#xD;
  &#xD;
                 -  Treatment with systemic immunosuppressive medication (including, but not limited&#xD;
                    to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide,&#xD;
                    and anti-tumor necrosis factor [TNF]-alpha agents) within 2 weeks prior to&#xD;
                    initiation of study treatment, or anticipation of need for systemic&#xD;
                    immunosuppressive medication during study treatment, with the following&#xD;
                    exceptions:&#xD;
  &#xD;
                      -  Patients who received acute, low-dose systemic immunosuppressant medication&#xD;
                         or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48&#xD;
                         hours of corticosteroids for a contrast allergy) are eligible for the study&#xD;
                         after principal investigator confirmation has been obtained&#xD;
  &#xD;
                      -  Patients who received mineralocorticoids (e.g., fludrocortisone),&#xD;
                         corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma&#xD;
                         or mitotane-associated adrenal insufficiency, or low-dose corticosteroids&#xD;
                         for orthostatic hypotension or other causes of adrenal insufficiency are&#xD;
                         eligible for the study&#xD;
  &#xD;
                      -  Inhaled, intranasal, intra-articular, or topical steroids are permitted&#xD;
  &#xD;
                 -  Active infection requiring systemic treatment. Acute or chronic hepatitis B or C&#xD;
                    infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency&#xD;
                    syndrome (AIDS)-related illness, or known positive test for tuberculosis&#xD;
                    infection where there is clinical or radiographic evidence of active&#xD;
                    mycobacterial infection&#xD;
  &#xD;
                 -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to&#xD;
                    initiation of study treatment&#xD;
  &#xD;
                 -  Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract&#xD;
                    infection or chronic obstructive pulmonary disease exacerbation) are eligible for&#xD;
                    the study&#xD;
  &#xD;
                 -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced&#xD;
                    pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on&#xD;
                    screening chest CT scan&#xD;
  &#xD;
                      -  History of radiation pneumonitis in the radiation field (fibrosis) is&#xD;
                         permitted&#xD;
  &#xD;
                 -  Serious non-healing wound/ulcer/bone fracture&#xD;
  &#xD;
                 -  Malabsorption syndrome&#xD;
  &#xD;
                 -  Uncompensated/symptomatic hypothyroidism&#xD;
  &#xD;
                 -  Moderate to severe hepatic impairment (Child-Pugh B or C)&#xD;
  &#xD;
                 -  Requirement for hemodialysis or peritoneal dialysis&#xD;
  &#xD;
                 -  History of solid organ or allogenic stem cell transplant&#xD;
  &#xD;
                 -  Known history of COVID-19 unless the subject has clinically recovered from the&#xD;
                    disease at least 30 days prior to first dose of study treatment&#xD;
  &#xD;
                 -  Severe infection within 4 weeks prior to initiation of study treatment,&#xD;
                    including, but not limited to, hospitalization for complications of infection,&#xD;
                    bacteremia, or severe pneumonia, or any active infection that could impact&#xD;
                    patient safety&#xD;
  &#xD;
            -  Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain&#xD;
               metastasis) within 2 weeks before first dose of study treatment. Minor surgeries&#xD;
               within 10 days before first dose of study treatment. Subjects must have complete wound&#xD;
               healing from major surgery or minor surgery before first dose of study treatment.&#xD;
               Subjects with clinically relevant ongoing complications from prior surgery are not&#xD;
               eligible&#xD;
  &#xD;
            -  Corrected QT interval calculated by the Fridericia formula (QTcF) &gt; 500 ms per&#xD;
               electrocardiogram (ECG) within 14 days before first dose of study treatment.&#xD;
               Furthermore, subjects with a history of additional risk factors for torsades de&#xD;
               pointes (e.g., long QT syndrome) are also excluded. Note: If a single ECG shows a QTcF&#xD;
               with an absolute value &gt; 500 ms, two additional ECGs at intervals of approximately 3&#xD;
               min must be performed within 30 min after the initial ECG, and the average of these&#xD;
               three consecutive results for QTcF will be used to determine eligibility&#xD;
  &#xD;
            -  Pregnant or lactating females&#xD;
  &#xD;
            -  Inability to swallow tablets or unwillingness or inability to receive IV&#xD;
               administration&#xD;
  &#xD;
            -  Previously identified allergy or hypersensitivity to components of the study treatment&#xD;
               formulations or history of severe infusion-related reactions to monoclonal antibodies.&#xD;
               Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase&#xD;
               deficiency or glucose-galactose malabsorption are also excluded&#xD;
  &#xD;
            -  Any other active malignancy at time of first dose of study treatment or diagnosis of&#xD;
               another malignancy within 3 years prior to first dose of study treatment that requires&#xD;
               active treatment, except for locally curable cancers that have been apparently cured,&#xD;
               such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma&#xD;
               in situ of the prostate, cervix, or breast&#xD;
  &#xD;
            -  Current treatment with anti-viral therapy for HBV&#xD;
  &#xD;
            -  History of leptomeningeal disease&#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>Bassel Nazha, MD, MPH</last_name>
      <role>Principal Investigator</role>
      <affiliation>Emory University Hospital/Winship Cancer Institute</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Bassel Nazha, MD, MPH</last_name>
      <phone>404-778-1900</phone>
      <email>bassel.nazha@emory.edu</email>
    </overall_contact>
    <location>
      <facility>
        <name>Emory University Hospital Midtown</name>
        <address>
          <city>Atlanta</city>
          <state>Georgia</state>
          <zip>30308</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Wilena Session</last_name>
        <email>wsessio@emory.edu</email>
      </contact>
      <investigator>
        <last_name>Bassel Nazha, MD, MPH</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Emory University Hospital/Winship Cancer Institute</name>
        <address>
          <city>Atlanta</city>
          <state>Georgia</state>
          <zip>30322</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Wilena Session</last_name>
        <email>wsessio@emory.edu</email>
      </contact>
      <investigator>
        <last_name>Bassel Nazha, MD, MPH</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 17, 2023</study_first_submitted>
    <study_first_submitted_qc>August 17, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 23, 2023</study_first_posted>
    <last_update_submitted>August 17, 2023</last_update_submitted>
    <last_update_submitted_qc>August 17, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 23, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Emory University</investigator_affiliation>
      <investigator_full_name>Bassel Nazha</investigator_full_name>
      <investigator_title>Principal Investigator</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carcinoma</mesh_term>
      <mesh_term>Adrenocortical Carcinoma</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Atezolizumab</mesh_term>
      <mesh_term>Antibodies, Monoclonal</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06006013
  org study id: STUDY00005532
  secondary id: NCI-2023-04952
  secondary id: STUDY00005532
  secondary id: WINSHIP5823-22
  secondary id: P30CA138292
  nct id: NCT06006013
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: No
  This phase II trial tests how well cabozantinib in combination with atezolizumab works in
        treating patients with adrenal cortical cancer that has spread to nearby tissue or lymph
        nodes (locally advanced), that has spread from where it first started (primary site) to other
        places in the body (metastatic), or that cannot be removed by surgery (unresectable).
        Cabozantinib inhibits receptor tyrosine kinases, which are receptors commonly over-expressed
        by tumor cells. This may result in an inhibition of both tumor growth and blood vessel
        formation, eventually leading to a decrease in tumor size or extent in the body.
        Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune
        system attack the cancer, and may interfere with the ability of tumor cells to grow and
        spread. Adding cabozantinib to atezolizumab may be more effective at treating patients with
        adrenal cortical cancer than giving these drugs alone.
  PRIMARY OBJECTIVE:
  
        I. To evaluate the anti-tumor activity of the combination of cabozantinib S-malate
        (cabozantinib) and atezolizumab by assessing the overall response rate (ORR) as measured by
        Response Evaluation Criteria in Solid Tumors (RECIST 1.1.).
  
        SECONDARY OBJECTIVE:
  
        I. To evaluate the efficacy of the combination of cabozantinib and atezolizumab as measured
        by progression free survival and overall survival assessed up to 2 years, safety and
        tolerability of the combination.
  
        TERTIARY/EXPLORATORY OBJECTIVE:
  
        I. To assess tissue-based assays in archival tissue and correlative changes in peripheral
        T-cell subsets, myeloid derived suppressor cells (MDSC), blood inflammatory markers and
        cytokines.
  
        OUTLINE:
  
        Patients receive cabozantinib orally (PO) once daily (QD) on days 1-21 of each cycle and
        atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat
        every 21 days in the absence of disease progression or unacceptable toxicity. Patients also
        undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) at screening and
        then every 12 weeks on study and undergo collection of blood samples at screening, on study,
        and at end of treatment. Patients without archival tissue also undergo biopsy at screening.
  
        After completion of study treatment, patients are followed for 28 days and then up to 2 years
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Overall response rate (ORR)
  time frame: Every 12 weeks, assessed up to 2 years
  description: ORR is defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors version 1.1. ORR will be estimated by the Clopper-Pearson method with 95% confidence intervals. Descriptive statistics on continuous data will include means, medians, standard deviations, and ranges, while categorical data will be summarized using frequency counts and percentages. Will explore whether the sample size can inform on the association between ORR and demographics or molecular biomarkers by Fisher's exact test (categorical variables) and Wilcoxon rank-sum test (continuous variables) wherever appropriate (this analysis is exploratory in nature).
  measure: Progression free survival
  time frame: From treatment initiation until disease progression, death due to disease, or lost to follow up, assessed up to 2 years
  description: The Kaplan-Meier method will be used to estimate median event time (with 95% confidence interval).
  measure: Overall survival
  time frame: From treatment initiation until death due to any cause or loss to follow up, assessed up to 2 years
  description: The Kaplan-Meier method will be used to estimate median event time (with 95% confidence interval).
  measure: Incidence of adverse events
  time frame: Up to 2 years
  description: Evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Safety endpoints will be tabulated using frequency such as percent with at least one adverse event, percent for each grade, and percent with grade 3 or more adverse events.
  arm group label: Treatment (cabozantinib, atezolizumab)
  arm group type: Experimental
  description: Patients receive cabozantinib PO QD on days 1-21 of each cycle and atezolizumab IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI at screening and then every 12 weeks on study and undergo collection of blood samples at screening, on study, and at end of treatment. Patients without archival tissue also undergo biopsy at screening.
  intervention type: Biological
  intervention name: Atezolizumab
  description: Given IV
  arm group label: Treatment (cabozantinib, atezolizumab)
  other name: MPDL 3280A
  other name: MPDL 328OA
  other name: MPDL-3280A
  other name: MPDL3280A
  other name: MPDL328OA
  other name: RG7446
  other name: RO5541267
  other name: Tecentriq
  intervention type: Procedure
  intervention name: Biopsy
  description: Undergo biopsy
  arm group label: Treatment (cabozantinib, atezolizumab)
  other name: BIOPSY_TYPE
  other name: Bx
  intervention type: Procedure
  intervention name: Biospecimen Collection
  description: Undergo collection of blood samples
  arm group label: Treatment (cabozantinib, atezolizumab)
  other name: Biological Sample Collection
  other name: Biospecimen Collected
  other name: Specimen Collection
  intervention type: Drug
  intervention name: Cabozantinib S-malate
  description: Given PO
  arm group label: Treatment (cabozantinib, atezolizumab)
  other name: BMS-907351
  other name: Cabometyx
  other name: Cometriq
  other name: XL-184
  other name: XL184
  intervention type: Procedure
  intervention name: Computed Tomography
  description: Undergo CT
  arm group label: Treatment (cabozantinib, atezolizumab)
  other name: CAT
  other name: CAT Scan
  other name: Computed Axial Tomography
  other name: Computerized Axial Tomography
  other name: Computerized axial tomography (procedure)
  other name: Computerized Tomography
  other name: CT
  other name: CT Scan
  other name: tomography
  intervention type: Procedure
  intervention name: Magnetic Resonance Imaging
  description: Undergo MRI
  arm group label: Treatment (cabozantinib, atezolizumab)
  other name: Magnetic Resonance
  other name: Magnetic resonance imaging (procedure)
  other name: Magnetic Resonance Imaging Scan
  other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  other name: MR
  other name: MR Imaging
  other name: MRI
  other name: MRI Scan
  other name: NMR Imaging
  other name: NMRI
  other name: Nuclear Magnetic Resonance Imaging
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Bassel Nazha, MD, MPH
  role: Principal Investigator
  affiliation: Emory University Hospital/Winship Cancer Institute
  last name: Bassel Nazha, MD, MPH
  phone: 404-778-1900
  email: bassel.nazha@emory.edu
  facility: 
  contact: 
  investigator: 
  facility: 
  contact: 
  investigator: 
  country: United States
  responsible party type: Principal Investigator
  investigator affiliation: Emory University
  investigator full name: Bassel Nazha
  investigator title: Principal Investigator
  mesh term: Carcinoma
  mesh term: Adrenocortical Carcinoma
  mesh term: Atezolizumab
  mesh term: Antibodies, Monoclonal