Efficacy of Adjuvant Mitotane Treatment (ADIUVO)

Condition(s) targeted: Adrenocortical Carcinoma

Intervention: MITOTANE (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: University of Turin, Italy

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

Overall contact:
Paola Perotti, Phone: +390119026, Ext: 643, Email: oncotrial.sanluigi@gmail.com

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

Official title: Efficacy of Adjuvant Mitotane Treatment in Prolonging Recurrence-free Survival in Patients With Adrenocortical Carcinoma at Low-intermediate Risk of Recurrence

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Disease Free survival

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.

Inclusion Criteria · Histologically confirmed diagnosis of ACC· Low-intermediate risk of relapse defined as: · Stage I-III ACC· Microscopically complete resection, defined as no evidence of microscopic residual disease based on surgical reports, histopathology and post-operative imaging· Ki 67 < 10%· Age > 18 years· ECOG performance status 0-2· 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. · Repeated 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, ALT) >3 times the upper normal range). Creatinine clearance may be calculated according to validated formulas (Cockcroft'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· 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Paola Perotti, Phone: +390119026, Ext: 643, Email: oncotrial.sanluigi@gmail.com

University Hospital Campus Mitte Charitè, Berlin, Berlin 10117, Germany; Recruiting
Marcus PD Quinkler, Phone: 030-450, Ext: 514259, Email: marcus.quinkler@charite.de
Marcus Quinkler, MD, Principal Investigator

University Hospital of Dresden, Dresden 01307, Germany; Recruiting
Stefan Bornstein, MD, Phone: 0351-458, Ext: 5955, Email: stefan.bornstein@uniklinikum-dresden.de
Stefan Bornstein, MD, Principal Investigator

University Hospital of Düsseldorf, Düsseldorf 40001, Germany; Not yet recruiting
Holger Willenberg, MD, Email: Holger.Willenberg@uni-duesseldorf.de
Holger Willenberg, Principal Investigator

University Hospital ENDOC of Hamburg, Hamburg 20357, Germany; Not yet recruiting
Stephan Petersenn, MD, Phone: 040-401, Ext: 87985, Email: stephan.petersenn@endoc-med.de
Stephan Petersenn, Principal Investigator

University Medicin Centre of Munchen, München 80336, Germany; Recruiting
Felix Beuschlein, MD, Phone: 089 -5160, Ext: 2110, Email: felix.beuschlein@med.uni-muenchen.de
Felix Beuschlein, Principal Investigator

University Hospital Wuerzburg, Endocrinology, Wurzburg 97080, Germany; Recruiting
Martin MD Fassnacht, Phone: 0931-201-, Ext: 39021, Email: Fassnacht_M@medizin.uni-wuerzburg.de
Martin Fassnacht, MD, Principal Investigator

Università degli studi di Firenze, Firenze, Italy; Not yet recruiting
Massimo Mannelli
Massimo Mannelli, Sub-Investigator

Azienda Ospedaliera di Foggia, Foggia, Italy; Active, not recruiting

Ospedale Cà Granda-Niguarda-Milano, Milano, Italy; Recruiting
Paola Loli
Paola Loli, Sub-Investigator

Azienda Ospedaliera San Luigi, Orbassano 10043, Italy; Recruiting
Paola Perotti, Phone: +390119026, Ext: 017, Email: oncotrial.sanluigi@gmail.com

Department of Clinical and Biological Sciences, University of Turin, Orbassano 10043, Italy; Recruiting
Paola Perotti, Phone: +390119026, Ext: 017, Email: oncotrial.sanluigi@gmail.com
Fulvia Daffara, MD, Sub-Investigator

Azienda Ospedaliera Padova, Padova, Italy; Active, not recruiting

Università degli studi di Palermo, Palermo, Italy; Not yet recruiting
Vittorio Gebbia

Policlinico Universitario A. Gemelli, Roma, Italy; Active, not recruiting

A.O.U. San Giovanni Battista - Molinette, Torino, Italy; Active, not recruiting

Dept. of Internal Medicine Maxima Medisch Centrum, Eindhoven 5600 PD, Netherlands; Active, not recruiting

A.O.Universitaria Arcispedale S.Anna Ferrara, Ferrara, Fe 44100, Italy; Recruiting
Prof. Ettore Degli Uberti
Ettore Degli Uberti, Principal Investigator

study website

Related 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.

Starting date: April 2008
Last updated: March 11, 2011