<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/NCT03257891</url>
  </required_header>
  <id_info>
    <org_study_id>NP2729</org_study_id>
    <nct_id>NCT03257891</nct_id>
  </id_info>
  <brief_title>Cabazitaxel Activity in Patients With Advanced AdrenoCortical-Carcinoma Progressing After Previous Chemotherapy Lines</brief_title>
  <acronym>CabACC</acronym>
  <official_title>Multicenter, Prospective, Non-randomized, Phase II Trial Designed to Evaluate the Activity of Cabazitaxel in Patients With Advanced Adreno-Cortical- Carcinoma Progressing After Previous Chemotherapy Lines</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>San Luigi Gonzaga Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Adrenocortical cancer (ACC) is a rare aggressive tumor. The treatment of metastatic ACC is&#xD;
      challenging and the current available treatments are mitotane, chemotherapy or the&#xD;
      combination of both. Prognosis in locally advanced inoperable and metastatic ACC patients&#xD;
      still remains poor, the 5-year overall survival being &lt;15%. New treatment strategies are&#xD;
      therefore needed. The taxanes are a class of drugs targeting the microtubules that have shown&#xD;
      to be effective in the treatment of several malignancies but have not been fully developed in&#xD;
      patients with ACC. Cabazitaxel is a new taxoid which promotes the tubulin assembly in vitro&#xD;
      and stabilizes microtubules against cold-induced depolymerization as efficiently as&#xD;
      docetaxel. Cabazitaxel was selected for development based on a better antiproliferative&#xD;
      activity on resistant cell lines than docetaxel. The activity of the drug against several&#xD;
      malignancies is currently tested in ongoing prospective studies, but to our knowledge neither&#xD;
      preclinical nor clinical studies are currently testing cabaztaxel in ACC. This study is aimed&#xD;
      to demonstrate that cabazitaxel is active in ACC, but the drug was never tested before in&#xD;
      this clinical setting. A prospective, non-randomized, multicentre, open label, single arm,&#xD;
      phase II study will be conducted in patients with advanced ACC. The phase II study will be&#xD;
      conducted in 2 different Italian Institutions that are reference centers for ACC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      CABAZITAXEL ADMINISTRATION Cabazitaxel will be administered at dose of 25 mg/m2 every 3&#xD;
      weeks, administered by IV route in 1 hour, for a maximum of 6 total cycles. The drug will be&#xD;
      provided by Sanofi -Aventis S.p.A. Concomitant mitotane therapy will not be permitted however&#xD;
      mitotane will be maintained in patients with hormone secreting tumors. Cycle length for&#xD;
      cabazitaxel is 3 weeks. New cycles of therapy may not begin until Absolute Neutrophil Count&#xD;
      (ANC) ≥1500/mm3, platelet count ≥75 000/mm3, and non-hematological toxicities (except&#xD;
      alopecia) have recovered to baseline.&#xD;
&#xD;
      A maximum of 2 weeks delay is allowed between 2 treatment cycles.&#xD;
&#xD;
      PHARMACOKINETIC STUDY Another study aims will be to assess the toxicity of cabazitaxel&#xD;
      therapy in ACC patients. As mitotane notoriously interfere with the metabolism of several&#xD;
      drugs (11), an ancillary study will be conducted to assess the pharmacokinetic profile of&#xD;
      cabazitaxel in the patient population with hormone secreting tumors that will maintain&#xD;
      mitotane administration vs patients with non secreting ACC in which mitotane will be stopped.&#xD;
      Blood samples will be collected in lithium heparinized tubes at fixed time points before and&#xD;
      after drug infusion: Cycles 1 on Day 1 just before infusion, 30 min after start of infusion,&#xD;
      5 min before the end of 1-hour infusion (Tmax), 24 h, 48h and 96 h post-infusion. Cabazitaxel&#xD;
      serum concentrations will be measured in plasma using a validated liquid&#xD;
      chromatography-tandem mass spectrometry method: the Agilent 1260 Infinity LC equipped with an&#xD;
      Agilent 6460 Triple Quadrupole Mass Spectrometer (QQQ) in electrospray mode systems.&#xD;
&#xD;
      STATISTICAL ANALYSIS All data collected at baseline, including recorded and derived variables&#xD;
      will be described on all patients by means of summary descriptive statistics: mean, standard&#xD;
      deviation, median, min, max, 25th and 75th percentiles for continuous variables; absolute and&#xD;
      relative frequency for categorical variables. The relative frequencies will be calculated on&#xD;
      the total patients with and without missing data. Whenever possible the data will be&#xD;
      described by visit.&#xD;
&#xD;
      Chi square ore Fisher test, when applicable will be employed to compare categorical&#xD;
      variables. Student T-test and analysis of variance for parametric or Wilcoxon's matched pairs&#xD;
      signed-rank test and Friedman analysis of variance for non parametric data will be used to&#xD;
      compare paired data. Simple correlation analysis will be performed by Spearman rho&#xD;
      (coefficient of Spearman's rank correlation) for nonparametric distribution. Two-tailed tests&#xD;
      will be used for all comparisons and p &lt;0.05. All survival functions will computed using the&#xD;
      Kaplan-Meier method. Survival curves will be compared with the log rank test.&#xD;
&#xD;
      CONCOMITANT MEDICATION Concurrent treatment with strong inhibitors and strong inducers of&#xD;
      cytochrome P450 3A4 is not permitted. For patients who were receiving treatment with such&#xD;
      agents, a 2-week washout period is required prior to randomization. Concurrent participation&#xD;
      in another clinical trial or treatment with any other anti-cancer therapy is also not&#xD;
      permitted. The Investigator may prescribe any other concomitant medications as deemed&#xD;
      necessary.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 25, 2018</start_date>
  <completion_date type="Anticipated">January 24, 2022</completion_date>
  <primary_completion_date type="Anticipated">January 24, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>A prospective, non-randomized, multicentre, open label, single arm, phase II study will be conducted in patients with advanced ACC treated with Cabazitaxel</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To assess the clinical benefit after 4 months of the cabazitaxel in patients with locally advanced or metastatic ACC who progressed after cytotoxic therapy.</measure>
    <time_frame>4 months</time_frame>
    <description>CT scan evaluated according to RECIST 1.1 criteria</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of Objective Response Rates (ORR)</measure>
    <time_frame>Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year</time_frame>
    <description>ORR evaluated by RECIST criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of overall survival</measure>
    <time_frame>Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year</time_frame>
    <description>defined as the time from the date of the study start to date of death due to any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of quality of life</measure>
    <time_frame>Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year</time_frame>
    <description>EORTC quality of life questionnaire (QLQ)-C30 will be administered to patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of toxicity</measure>
    <time_frame>Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year</time_frame>
    <description>evaluated by NCI CTCAE V4.03 criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of hormone response</measure>
    <time_frame>Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year</time_frame>
    <description>Evaluation of adrenocorticotropic hormone (ACTH), Testosterone, Progesterone, Cortisol, (Deidroepiandrosterone) DHEA-S, 17-hydroxide- progesterone, Androstenedione in serum. Evaluation of 24 hours urinary cortisol.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>Adrenocortical Carcinoma</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>patients with advanced Adrenocortical- Carcinoma progressing after previous chemotherapy lines will be treated with Cabazitaxel</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabazitaxel</intervention_name>
    <description>Cabazitaxel will be administered every 21 days</description>
    <arm_group_label>Arm 1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed diagnosis of ACC&#xD;
&#xD;
          -  Locally advanced or metastatic disease not amenable to radical surgery resection&#xD;
&#xD;
          -  Radiologically monitorised disease&#xD;
&#xD;
          -  Progressing disease after one to three cytotoxic chemotherapy regimes (including a&#xD;
             platin-based protocol)&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2&#xD;
&#xD;
          -  Life expectancy ≥ 3 months&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Adequate bone marrow reserve (neutrophils ≥ 1500/mm³ and platelets &gt; 100.000/mm³)&#xD;
&#xD;
          -  Effective contraception in pre-menopausal female and male patients&#xD;
&#xD;
          -  Patient´s written informed consent&#xD;
&#xD;
          -  Ability to comply with the protocol procedures&#xD;
&#xD;
          -  Mitotane intake should be stopped one months before the study entry&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ&#xD;
             cervical carcinoma, or other treated malignancies with no evidence of disease for at&#xD;
             least three years.&#xD;
&#xD;
          -  Serum creatinine &gt; 1.5 x ULN or hepatic insufficiency, Hemoglobin &lt;10.0 g/dL;&#xD;
&#xD;
          -  Total bilirubin &gt;1x ULN, Creatinine &lt; 1.5 ULN;&#xD;
&#xD;
          -  Decompensated heart failure (ejection fraction &lt;45%), myocardial infarction or&#xD;
             revascularization procedure during the last 6 months, unstable angina pectoris,&#xD;
             uncontrolled cardiac arrhythmia&#xD;
&#xD;
          -  Pregnancy or breast feeding&#xD;
&#xD;
          -  Any other severe acute or chronic medical or psychiatric condition, or laboratory&#xD;
             abnormality that would impart, in the judgment of the investigator, excess risk&#xD;
             associated with study participation or study drug administration, or which, in the&#xD;
             judgment of the investigator, would make the patient inappropriate for entry into this&#xD;
             study&#xD;
&#xD;
          -  Patients with serum levels of mitotane (evaluated one week before the study start) in&#xD;
             the therapeutic range (14-20 mcg/ml).History of severe hypersensitivity reaction&#xD;
             (≥grade 3) to docetaxel&#xD;
&#xD;
          -  History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing&#xD;
             drugs&#xD;
&#xD;
          -  Uncontrolled severe illness or medical condition (including uncontrolled diabetes&#xD;
             mellitus)&#xD;
&#xD;
          -  Concurrent or planned treatment with strong inhibitors or strong inducers of&#xD;
             cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are&#xD;
             already on these treatments) (see Annex 1 and Annex 2)&#xD;
&#xD;
          -  Concomitant vaccination with yellow fever vaccine&#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>Alfredo Berruti, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Alfredo Berruti, MD</last_name>
    <phone>030399</phone>
    <phone_ext>5410</phone_ext>
    <email>alfredo.berruti@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Salvatore Grisanti, MD, PhD</last_name>
    <phone>030399</phone>
    <phone_ext>5260</phone_ext>
    <email>grisanti.salvatore@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Azienda Ospedaliera Spedali Civili di Brescia</name>
      <address>
        <city>Brescia</city>
        <zip>25123</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <results_reference>
    <citation>Berruti A, Ferrero A, Sperone P, Daffara F, Reimondo G, Papotti M, Dogliotti L, Angeli A, Terzolo M. Emerging drugs for adrenocortical carcinoma. Expert Opin Emerg Drugs. 2008 Sep;13(3):497-509. doi: 10.1517/14728214.13.3.497.</citation>
    <PMID>18764725</PMID>
  </results_reference>
  <results_reference>
    <citation>Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardiere C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Muller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. doi: 10.1056/NEJMoa1200966. Epub 2012 May 2.</citation>
    <PMID>22551107</PMID>
  </results_reference>
  <results_reference>
    <citation>Bates SE, Shieh CY, Mickley LA, Dichek HL, Gazdar A, Loriaux DL, Fojo AT. Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas. J Clin Endocrinol Metab. 1991 Jul;73(1):18-29. doi: 10.1210/jcem-73-1-18.</citation>
    <PMID>1675220</PMID>
  </results_reference>
  <results_reference>
    <citation>Chen KG, Sikic BI. Molecular pathways: regulation and therapeutic implications of multidrug resistance. Clin Cancer Res. 2012 Apr 1;18(7):1863-9. doi: 10.1158/1078-0432.CCR-11-1590. Epub 2012 Feb 16.</citation>
    <PMID>22344233</PMID>
  </results_reference>
  <results_reference>
    <citation>Berruti A, Sperone P, Ferrero A, Germano A, Ardito A, Priola AM, De Francia S, Volante M, Daffara F, Generali D, Leboulleux S, Perotti P, Baudin E, Papotti M, Terzolo M. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol. 2012 Mar;166(3):451-8. doi: 10.1530/EJE-11-0918. Epub 2011 Dec 21.</citation>
    <PMID>22189997</PMID>
  </results_reference>
  <results_reference>
    <citation>Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. doi: 10.1200/JCO.2005.04.937. Epub 2005 Sep 19.</citation>
    <PMID>16172456</PMID>
  </results_reference>
  <results_reference>
    <citation>Demeure MJ, Stephan E, Sinari S, Mount D, Gately S, Gonzales P, Hostetter G, Komorowski R, Kiefer J, Grant CS, Han H, Von Hoff DD, Bussey KJ. Preclinical investigation of nanoparticle albumin-bound paclitaxel as a potential treatment for adrenocortical cancer. Ann Surg. 2012 Jan;255(1):140-6. doi: 10.1097/SLA.0b013e3182402d21.</citation>
    <PMID>22156929</PMID>
  </results_reference>
  <results_reference>
    <citation>Mita AC, Figlin R, Mita MM. Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer? Clin Cancer Res. 2012 Dec 15;18(24):6574-9. doi: 10.1158/1078-0432.CCR-12-1584. Epub 2012 Oct 22.</citation>
    <PMID>23091116</PMID>
  </results_reference>
  <results_reference>
    <citation>Montoya M, Brown JW, Fishman LM. Comparative effects of chemotherapeutic agents on the growth and survival of human adrenal carcinoma cells in culture. Horm Metab Res. 2008 May;40(5):302-5. doi: 10.1055/s-2008-1073139.</citation>
    <PMID>18491247</PMID>
  </results_reference>
  <results_reference>
    <citation>Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol (Oxf). 2011 Nov;75(5):585-91. doi: 10.1111/j.1365-2265.2011.04214.x.</citation>
    <PMID>21883349</PMID>
  </results_reference>
  <results_reference>
    <citation>Hasegawa E, Nakagawa S, Sato M, Tachikawa E, Yamato S. Effect of polyphenols on production of steroid hormones from human adrenocortical NCI-H295R cells. Biol Pharm Bull. 2013;36(2):228-37. doi: 10.1248/bpb.b12-00627.</citation>
    <PMID>23370353</PMID>
  </results_reference>
  <results_reference>
    <citation>Arrighi N, Bodei S, Lucente A, Michel MC, Zani D, Simeone C, Cunico SC, Spano P, Sigala S. Muscarinic receptors stimulate cell proliferation in the human urothelium-derived cell line UROtsa. Pharmacol Res. 2011 Oct;64(4):420-5. doi: 10.1016/j.phrs.2011.06.009. Epub 2011 Jun 28.</citation>
    <PMID>21718784</PMID>
  </results_reference>
  <results_reference>
    <citation>Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.</citation>
    <PMID>2702835</PMID>
  </results_reference>
  <results_reference>
    <citation>Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005 Sep;12(3):657-66. doi: 10.1677/erc.1.01025.</citation>
    <PMID>16172198</PMID>
  </results_reference>
  <verification_date>April 2018</verification_date>
  <study_first_submitted>August 17, 2017</study_first_submitted>
  <study_first_submitted_qc>August 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 22, 2017</study_first_posted>
  <last_update_submitted>April 10, 2018</last_update_submitted>
  <last_update_submitted_qc>April 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</investigator_affiliation>
    <investigator_full_name>Alfredo Berruti</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>Adrenocortical Carcinoma</keyword>
  <keyword>Cabazitaxel</keyword>
  <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>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03257891
org study id: NP2729
nct id: NCT03257891
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Adrenocortical cancer (ACC) is a rare aggressive tumor. The treatment of metastatic ACC is
      challenging and the current available treatments are mitotane, chemotherapy or the
      combination of both. Prognosis in locally advanced inoperable and metastatic ACC patients
      still remains poor, the 5-year overall survival being <15%. New treatment strategies are
      therefore needed. The taxanes are a class of drugs targeting the microtubules that have shown
      to be effective in the treatment of several malignancies but have not been fully developed in
      patients with ACC. Cabazitaxel is a new taxoid which promotes the tubulin assembly in vitro
      and stabilizes microtubules against cold-induced depolymerization as efficiently as
      docetaxel. Cabazitaxel was selected for development based on a better antiproliferative
      activity on resistant cell lines than docetaxel. The activity of the drug against several
      malignancies is currently tested in ongoing prospective studies, but to our knowledge neither
      preclinical nor clinical studies are currently testing cabaztaxel in ACC. This study is aimed
      to demonstrate that cabazitaxel is active in ACC, but the drug was never tested before in
      this clinical setting. A prospective, non-randomized, multicentre, open label, single arm,
      phase II study will be conducted in patients with advanced ACC. The phase II study will be
      conducted in 2 different Italian Institutions that are reference centers for ACC.
CABAZITAXEL ADMINISTRATION Cabazitaxel will be administered at dose of 25 mg/m2 every 3
      weeks, administered by IV route in 1 hour, for a maximum of 6 total cycles. The drug will be
      provided by Sanofi -Aventis S.p.A. Concomitant mitotane therapy will not be permitted however
      mitotane will be maintained in patients with hormone secreting tumors. Cycle length for
      cabazitaxel is 3 weeks. New cycles of therapy may not begin until Absolute Neutrophil Count
      (ANC) ≥1500/mm3, platelet count ≥75 000/mm3, and non-hematological toxicities (except
      alopecia) have recovered to baseline.

      A maximum of 2 weeks delay is allowed between 2 treatment cycles.

      PHARMACOKINETIC STUDY Another study aims will be to assess the toxicity of cabazitaxel
      therapy in ACC patients. As mitotane notoriously interfere with the metabolism of several
      drugs (11), an ancillary study will be conducted to assess the pharmacokinetic profile of
      cabazitaxel in the patient population with hormone secreting tumors that will maintain
      mitotane administration vs patients with non secreting ACC in which mitotane will be stopped.
      Blood samples will be collected in lithium heparinized tubes at fixed time points before and
      after drug infusion: Cycles 1 on Day 1 just before infusion, 30 min after start of infusion,
      5 min before the end of 1-hour infusion (Tmax), 24 h, 48h and 96 h post-infusion. Cabazitaxel
      serum concentrations will be measured in plasma using a validated liquid
      chromatography-tandem mass spectrometry method: the Agilent 1260 Infinity LC equipped with an
      Agilent 6460 Triple Quadrupole Mass Spectrometer (QQQ) in electrospray mode systems.

      STATISTICAL ANALYSIS All data collected at baseline, including recorded and derived variables
      will be described on all patients by means of summary descriptive statistics: mean, standard
      deviation, median, min, max, 25th and 75th percentiles for continuous variables; absolute and
      relative frequency for categorical variables. The relative frequencies will be calculated on
      the total patients with and without missing data. Whenever possible the data will be
      described by visit.

      Chi square ore Fisher test, when applicable will be employed to compare categorical
      variables. Student T-test and analysis of variance for parametric or Wilcoxon's matched pairs
      signed-rank test and Friedman analysis of variance for non parametric data will be used to
      compare paired data. Simple correlation analysis will be performed by Spearman rho
      (coefficient of Spearman's rank correlation) for nonparametric distribution. Two-tailed tests
      will be used for all comparisons and p <0.05. All survival functions will computed using the
      Kaplan-Meier method. Survival curves will be compared with the log rank test.

      CONCOMITANT MEDICATION Concurrent treatment with strong inhibitors and strong inducers of
      cytochrome P450 3A4 is not permitted. For patients who were receiving treatment with such
      agents, a 2-week washout period is required prior to randomization. Concurrent participation
      in another clinical trial or treatment with any other anti-cancer therapy is also not
      permitted. The Investigator may prescribe any other concomitant medications as deemed
      necessary.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: A prospective, non-randomized, multicentre, open label, single arm, phase II study will be conducted in patients with advanced ACC treated with Cabazitaxel
primary purpose: Treatment
masking: None (Open Label)
measure: To assess the clinical benefit after 4 months of the cabazitaxel in patients with locally advanced or metastatic ACC who progressed after cytotoxic therapy.
time frame: 4 months
description: CT scan evaluated according to RECIST 1.1 criteria
measure: Assessment of Objective Response Rates (ORR)
time frame: Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
description: ORR evaluated by RECIST criteria
measure: Assessment of overall survival
time frame: Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
description: defined as the time from the date of the study start to date of death due to any cause
measure: Assessment of quality of life
time frame: Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
description: EORTC quality of life questionnaire (QLQ)-C30 will be administered to patients
measure: Assessment of toxicity
time frame: Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
description: evaluated by NCI CTCAE V4.03 criteria
measure: Assessment of hormone response
time frame: Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year
description: Evaluation of adrenocorticotropic hormone (ACTH), Testosterone, Progesterone, Cortisol, (Deidroepiandrosterone) DHEA-S, 17-hydroxide- progesterone, Androstenedione in serum. Evaluation of 24 hours urinary cortisol.
arm group label: Arm 1
arm group type: Experimental
description: patients with advanced Adrenocortical- Carcinoma progressing after previous chemotherapy lines will be treated with Cabazitaxel
intervention type: Drug
intervention name: Cabazitaxel
description: Cabazitaxel will be administered every 21 days
arm group label: Arm 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alfredo Berruti, MD
role: Principal Investigator
affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
last name: Alfredo Berruti, MD
phone: 030399
phone ext: 5410
email: alfredo.berruti@gmail.com
last name: Salvatore Grisanti, MD, PhD
phone: 030399
phone ext: 5260
email: grisanti.salvatore@gmail.com
facility: 
status: Recruiting
country: Italy
citation: Berruti A, Ferrero A, Sperone P, Daffara F, Reimondo G, Papotti M, Dogliotti L, Angeli A, Terzolo M. Emerging drugs for adrenocortical carcinoma. Expert Opin Emerg Drugs. 2008 Sep;13(3):497-509. doi: 10.1517/14728214.13.3.497.
PMID: 18764725
citation: Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardiere C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Muller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. doi: 10.1056/NEJMoa1200966. Epub 2012 May 2.
PMID: 22551107
citation: Bates SE, Shieh CY, Mickley LA, Dichek HL, Gazdar A, Loriaux DL, Fojo AT. Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas. J Clin Endocrinol Metab. 1991 Jul;73(1):18-29. doi: 10.1210/jcem-73-1-18.
PMID: 1675220
citation: Chen KG, Sikic BI. Molecular pathways: regulation and therapeutic implications of multidrug resistance. Clin Cancer Res. 2012 Apr 1;18(7):1863-9. doi: 10.1158/1078-0432.CCR-11-1590. Epub 2012 Feb 16.
PMID: 22344233
citation: Berruti A, Sperone P, Ferrero A, Germano A, Ardito A, Priola AM, De Francia S, Volante M, Daffara F, Generali D, Leboulleux S, Perotti P, Baudin E, Papotti M, Terzolo M. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol. 2012 Mar;166(3):451-8. doi: 10.1530/EJE-11-0918. Epub 2011 Dec 21.
PMID: 22189997
citation: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. doi: 10.1200/JCO.2005.04.937. Epub 2005 Sep 19.
PMID: 16172456
citation: Demeure MJ, Stephan E, Sinari S, Mount D, Gately S, Gonzales P, Hostetter G, Komorowski R, Kiefer J, Grant CS, Han H, Von Hoff DD, Bussey KJ. Preclinical investigation of nanoparticle albumin-bound paclitaxel as a potential treatment for adrenocortical cancer. Ann Surg. 2012 Jan;255(1):140-6. doi: 10.1097/SLA.0b013e3182402d21.
PMID: 22156929
citation: Mita AC, Figlin R, Mita MM. Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer? Clin Cancer Res. 2012 Dec 15;18(24):6574-9. doi: 10.1158/1078-0432.CCR-12-1584. Epub 2012 Oct 22.
PMID: 23091116
citation: Montoya M, Brown JW, Fishman LM. Comparative effects of chemotherapeutic agents on the growth and survival of human adrenal carcinoma cells in culture. Horm Metab Res. 2008 May;40(5):302-5. doi: 10.1055/s-2008-1073139.
PMID: 18491247
citation: Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol (Oxf). 2011 Nov;75(5):585-91. doi: 10.1111/j.1365-2265.2011.04214.x.
PMID: 21883349
citation: Hasegawa E, Nakagawa S, Sato M, Tachikawa E, Yamato S. Effect of polyphenols on production of steroid hormones from human adrenocortical NCI-H295R cells. Biol Pharm Bull. 2013;36(2):228-37. doi: 10.1248/bpb.b12-00627.
PMID: 23370353
citation: Arrighi N, Bodei S, Lucente A, Michel MC, Zani D, Simeone C, Cunico SC, Spano P, Sigala S. Muscarinic receptors stimulate cell proliferation in the human urothelium-derived cell line UROtsa. Pharmacol Res. 2011 Oct;64(4):420-5. doi: 10.1016/j.phrs.2011.06.009. Epub 2011 Jun 28.
PMID: 21718784
citation: Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.
PMID: 2702835
citation: Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005 Sep;12(3):657-66. doi: 10.1677/erc.1.01025.
PMID: 16172198
responsible party type: Principal Investigator
investigator affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
investigator full name: Alfredo Berruti
investigator title: MD
mesh term: Carcinoma
mesh term: Adrenocortical Carcinoma
sharing ipd: Undecided