Efficacy of Adjuvant Mitotane Treatment (ADIUVO) (ADIUVO)

Study Description

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Brief Summary:

Study Rationale Adrenocortical carcinoma (ACC) is a very rare disease with a high risk of relapse after radical surgery. The efficacy of adjuvant mitotane treatment is suggested by a retrospective multicenter international study showing that postoperative mitotane treatment was associated with a significant reduction of the risk of relapse and death. However, these promising results need confirmation in a randomized prospective study. Caution should be adopted particularly in patients with low risk of disease relapse, in whom the benefit of therapy should be weighted against the side effects. Even if an adjuvant treatment seems justified in patients at high risk of relapse, a randomised prospective study is needed to assess whether such a treatment is efficacious in patients at low-intermediate risk.

The purpose of the present study is to determine whether adjuvant mitotane treatment is effective in prolonging the disease free survival in patients with adrenocortical carcinoma at low-intermediate risk of progression who underwent radical resection

Condition or disease	Intervention/treatment	Phase
Adrenocortical Carcinoma	Drug: MITOTANE	Phase 3

Detailed Description:

Endpoints Primary : To compare DFS (Disease Free Survival), defined as the time between the date of randomization until documentation of any of the following failures (whichever occurs first): -local or distant recurrence of disease;-death from any cause or completion of follow-up.

Secondary:

To compare OS (Overall Survival), defined as the time interval between the date of randomization and the date of death from any cause or the last known alive date;· To compare quality of life measured by EORTC-QLQ-C30· To compare toxicity, graded according to the NCI-CTG criteria;· To compare DFS and OS in patients who achieve or not serum mitotane concentrations > 14 mg/L;· To compare DFS and OS between the 2 arms in patients subgroups stratified according to: type of hormone secretion, stage of disease, histopathologic characteristics.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	200 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Efficacy of Adjuvant Mitotane Treatment in Prolonging Recurrence-free Survival in Patients With Adrenocortical Carcinoma at Low-intermediate Risk of Recurrence
Study Start Date :	April 2008
Estimated Primary Completion Date :	December 2018
Estimated Study Completion Date :	December 2020

Arms and Interventions

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Arm	Intervention/treatment
No Intervention: Follow-up; Arm B
Experimental: Mitotane; Arm A	Drug: MITOTANE; mitotane will be administered at a starting dose of 1.5 g/day and increased in case of good gastrointestinal tolerance on day 2 to 3 g/day, on day 3 to 4.5 g/day, and on day 4 to 6 g/day. A dose of 6 g/day will be administered until first mitotane blood level is assessed. Further adjustment of dosage will be performed according to blood concentrations and tolerability.; Other Name: Mitotane (Lysodren)

Outcome Measures

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Primary Outcome Measures :

1. Disease Free survival [ Time Frame: Till the last follow up ]
   Survival in years

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Histologically confirmed diagnosis of ACC according to Weiss system by a national reference pathologist who has to be nominated before study initiation.

• Low-intermediate risk of relapse defined as:

  • Stage I-III (according to ENSAT classification 2008; see Appendix 2)
  • Microscopically complete resection, defined as no evidence of microscopic residual disease based on surgical reports, histopathology and post-operative imaging. Detailed pathological and surgical reports prepared according to guidelines detailed in appendix x and y should be available for assessment.
  • Ki 67 < 10%
• Post-operative imaging (thoracic and whole abdominal CT with contrast medium or MRI) demonstrating no evidence of disease within 4 weeks from randomization
• Age > 18 years
• ECOG performance status 0-2 (Appendix 3)
• Adequate bone marrow reserve (neutrophils > 1000/mm3 and platelets > 80000/ mm3)
• Ability to comply with the protocol procedures (including geographic accessibility)
• Written informed consent

Exclusion Criteria:

• Time between primary surgery and randomization > 3 months.
• Repeat surgery for recurrence of disease
• Presence of autonomous adrenocortical hormone secretion despite the absence of disease detectable with imaging techniques
• History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other treated malignancies with no evidence of disease for at least three years
• Renal insufficiency (creatinine clearance < 40 ml/min) or liver insufficiency (serum bilirubin > 2 times the upper normal range and/or serum transaminases (AST/SGOT, ALT/SGPT, but not gamma Glutamyl Transpeptidase) >3 times the upper normal range). Creatinine clearance may be calculated according to validated formulas (Crockoft's or MDRD)
• Pregnancy or breast feeding
• Previous or current treatment with mitotane or other antineoplastic drugs for ACC
• Previous radiotherapy of the tumor bed (for ACC).
• Any other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Paola Perotti	+390119026 ext 643	oncotrial.sanluigi@gmail.com
Contact: Paola Sperone	+390119026 ext 017	paola.sperone@email.it

Locations

United States, Maryland
Medical Oncology Branch - Center for Cancer Research - National Cancer Institute	Recruiting
Bethesda, Maryland, United States, 20892-1903
Contact: Tito Fojo fojot@mail.nih.gov
Contact: Maureen Edgerly 301-435 ext 5604 edgerlym@mail.nih.gov
Principal Investigator: Tito Fojo
United States, Michigan
Endocrine Oncology - University of Michigan Comprehensive Cancer Center	Active, not recruiting
Ann Arbor, Michigan, United States, 48109-0921
Canada
Endocrinologie - Centre hospitalier de l'Université de Montréal (CHUM)	Recruiting
Montreal, Canada, 3840
Contact: André Lacroix andre.lacroix@umontreal.ca
Principal Investigator: André Lacroix
France
Endocrinologie - CHU Besançon Hôpital Jean Minjoz	Recruiting
Besancon, France, 25000
Contact: Alfred Perforinis alfred.penfornis@univ-fcomte.fr
Contact: Annie Clergeot aclergeot@chu-besancon.fr
Principal Investigator: Alfred Penfornis
Endocrinologie - CHU Lyon Hôpital Pierre Wertheimer	Recruiting
Bron, France, 69677
Contact: Michel Pugeat michel.pugeat@chu-lyon.fr
Contact: Cecilie Nozieres cecile.nozieres@chu-lyon.fr
Principal Investigator: Michel Pugeat
Endocrinologie - Hôpital A. Michallon	Recruiting
La Tronche, France, 38700
Contact: Olivier Cabre 33 04 76 76 ext 5175 OlivierChabre@chu-grenoble.fr
Principal Investigator: Olivier Cabre
Endocrinologie - Cochin, APHP	Recruiting
Paris, France, 75679
Contact: Bertagna Xavier +330158 ext 411790 xavier.bertagna@cch.aphp.fr
Contact: Rossella Libè +330158 ext 413249 Emrossella.libe@cch.aphp.fr
Principal Investigator: Xavier Bertagna
Sub-Investigator: Rossella Libè
Endocrinologie - CHU Toulouse Hôpital Larrey	Recruiting
Toulouse, France
Contact: Philippe Caron caron.p@chu-toulouse.fr
Contact: Delphine Vezzosi vezzosi.d@chu-toulouse.fr
Principal Investigator: Philippe Caron
Endocrinologie - Institut de Cancérologie Gustave Roussy	Recruiting
Villejuif, France, 94805
Contact: Eric Baudin +330142 ext 114242 eric.baudin@igr.fr
Contact: Cécile CHOUGNET +330142 ext 115224 Cecile.chougnet@igr.fr
Principal Investigator: Eric Baudin
Germany
University Hospital Campus Mitte Charitè, Berlin	Recruiting
Berlin, Germany, 10117
Contact: Marcus PD Quinkler 030-450 ext 514259 marcus.quinkler@charite.de
Principal Investigator: Marcus Quinkler, MD
University Hospital of Dresden	Recruiting
Dresden, Germany, 01307
Contact: Stefan Bornstein, MD 0351-458 ext 5955 stefan.bornstein@uniklinikum-dresden.de
Principal Investigator: Stefan Bornstein, MD
University Hospital of Düsseldorf	Not yet recruiting
Düsseldorf, Germany, 40001
Contact: Holger Willenberg, MD Holger.Willenberg@uni-duesseldorf.de
Principal Investigator: Holger Willenberg
Center for Endocrine Tumors - ENDOC	Recruiting
Hamburg, Germany, 20357
Contact: Stephan Petersenn, MD 040-401 ext 87985 stephan.petersenn@endoc-med.de
Principal Investigator: Stephan Petersenn
University Medicin Centre of Munchen	Recruiting
München, Germany, 80336
Contact: Felix Beuschlein, MD 089 -5160 ext 2110 felix.beuschlein@med.uni-muenchen.de
Contact: Martin Fassnacht Fassnacht_m@medizin.uni-wuerzburg.de
Principal Investigator: Felix Beuschlein
University Hospital Wuerzburg, Endocrinology	Recruiting
Wurzburg, Germany, 97080
Contact: Martin MD Fassnacht 0931-201- ext 39021 Fassnacht_M@medizin.uni-wuerzburg.de
Contact: Patricia Sculler Schuller_P@medizin.uni-wuerzburg.de
Principal Investigator: Martin Fassnacht, MD
Italy
A.O.Universitaria Arcispedale S.Anna Ferrara	Recruiting
Ferrara, Fe, Italy, 44100
Contact: Prof. Ettore Degli Uberti
Principal Investigator: Ettore Degli Uberti
UO Oncologia Medica - AO Spedali Civili	Recruiting
Brescia, Italy, 25123
Contact: Alfredo Berruti alfredo.berruti@gmail.com
Contact: Anna Scalvini annascalvini@gmail.com
Principal Investigator: Alfredo Berruti
Università degli studi di Firenze	Not yet recruiting
Firenze, Italy
Contact: Massimo Mannelli
Sub-Investigator: Massimo Mannelli
Azienda Ospedaliera di Foggia	Active, not recruiting
Foggia, Italy
Ospedale Cà Granda-Niguarda-Milano	Recruiting
Milano, Italy
Contact: Paola Loli
Sub-Investigator: Paola Loli
Azienda Ospedaliera San Luigi	Recruiting
Orbassano, Italy, 10043
Contact: Paola Perotti +390119026 ext 017 oncotrial.sanluigi@gmail.com
Department of Clinical and Biological Sciences, University of Turin, Internal Medicine 1	Recruiting
Orbassano, Italy, 10043
Contact: Paola Perotti +390119026 ext 513 oncotrial.sanluigi@gmail.com
Principal Investigator: Massimo Terzolo, MD
Azienda Ospedaliera Padova	Active, not recruiting
Padova, Italy
Università degli studi di Palermo	Not yet recruiting
Palermo, Italy
Contact: Vittorio Gebbia
Policlinico Universitario A. Gemelli	Active, not recruiting
Roma, Italy
A.O.U. San Giovanni Battista - Molinette	Recruiting
Torino, Italy
Contact: Enzo Gigo, MD
Principal Investigator: Enzo Ghigo
Netherlands
Dept. of Internal Medicine Maxima Medisch Centrum	Recruiting
Eindhoven, Netherlands, 5600 PD
Principal Investigator: Harm Haak, MD
United Kingdom
Cancer Research UK Clinical Trials Unit (CRCTU) - School of Cancer Sciences - University of Birmingham	Not yet recruiting
Birmingham, Edgbaston, United Kingdom, 152TT
Contact: Wiebke Arlt w.arlt@bham.ac.uk
Contact: Ana Huges a.i.hughes@bham.ac.uk
Principal Investigator: Wiebke Arlt

Sponsors and Collaborators

University of Turin, Italy

Investigators

Study Chair:	Massimo Terzolo, MD	Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, Italy
Study Director:	Martin Fassnacht, MD	Department of Internal Medicine, University of Wuerzburg, Germany
Study Chair:	Alfredo Berruti, MD	Medical Oncology, Department of Clinical and Biological Sciences, University of Turin
Principal Investigator:	Eric Baudin, MD	Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave Roussy, Villejuif, France.
Principal Investigator:	Harm Haak, MD	Department of Internal Medicine, Máxima Medical Centre, Eindhoven, The Netherlands

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

study website 

Publications:

Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007 Jun 7;356(23):2372-80.

Responsible Party:	Alfredo Berruti, Prof., University of Turin, Italy
ClinicalTrials.gov Identifier:	NCT00777244 History of Changes
Other Study ID Numbers:	EudraCT 2007-007262-38
First Posted:	October 22, 2008
Last Update Posted:	May 8, 2017
Last Verified:	May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Alfredo Berruti, University of Turin, Italy:

mitotane; adjuvant therapy; disease free survival

Additional relevant MeSH terms:

Adrenal Gland Neoplasms; Carcinoma; Adrenocortical Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Adrenal Cortex Neoplasms	Endocrine Gland Neoplasms; Neoplasms by Site; Adrenal Cortex Diseases; Adrenal Gland Diseases; Endocrine System Diseases; Mitotane; Antineoplastic Agents, Hormonal; Antineoplastic Agents