Clinical trial NCT00777244: Efficacy of Adjuvant Mitotane Treatment (ADIUVO)
Official title: Efficacy of Adjuvant Mitotane Treatment in Prolonging Recurrence-free Survival in Patients With Adrenocortical Carcinoma at Low-intermediate Risk of Recurrence
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Adrenocortical Carcinoma
Keywords: mitotane
adjuvant therapy
disease free survival
Lead sponsor: University of Turin, Italy
Sponsor class: OTHER
First posted: 2008-10-22
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility 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.

Primary outcomes:
measure: Disease Free survival
timeFrame: Till the last follow up
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Medical Oncology Branch - Center for Cancer Research - National Cancer Institute
state: Maryland
city: Ann Arbor
country: United States
facility: Endocrine Oncology - University of Michigan Comprehensive Cancer Center
state: Michigan
city: Montreal
country: Canada
facility: Endocrinologie - Centre hospitalier de l'Université de Montréal (CHUM)
city: Besancon
country: France
facility: Endocrinologie - CHU Besançon Hôpital Jean Minjoz
city: Bron
country: France
facility: Endocrinologie - CHU Lyon Hôpital Pierre Wertheimer
city: La Tronche
country: France
facility: Endocrinologie - Hôpital A. Michallon
city: Paris
country: France
facility: Endocrinologie - Cochin, APHP
city: Toulouse
country: France
facility: Endocrinologie - CHU Toulouse Hôpital Larrey
city: Villejuif
country: France
facility: Endocrinologie - Institut de Cancérologie Gustave Roussy
city: Berlin
country: Germany
facility: University Hospital Campus Mitte Charitè, Berlin
city: Dresden
country: Germany
facility: University Hospital of Dresden
city: Düsseldorf
country: Germany
facility: University Hospital of Düsseldorf
city: Hamburg
country: Germany
facility: Center for Endocrine Tumors - ENDOC
city: München
country: Germany
facility: University Medicin Centre of Munchen
city: Wurzburg
country: Germany
facility: University Hospital Wuerzburg, Endocrinology
city: Ferrara
country: Italy
facility: A.O.Universitaria Arcispedale S.Anna Ferrara
state: Fe
city: Brescia
country: Italy
facility: UO Oncologia Medica - AO Spedali Civili
city: Firenze
country: Italy
facility: Università degli studi di Firenze
city: Foggia
country: Italy
facility: Azienda Ospedaliera di Foggia
city: Milano
country: Italy
facility: Ospedale Cà Granda-Niguarda-Milano
city: Orbassano
country: Italy
facility: Azienda Ospedaliera San Luigi
city: Orbassano
country: Italy
facility: Department of Clinical and Biological Sciences, University of Turin, Internal Medicine 1
city: Padova
country: Italy
facility: Azienda Ospedaliera Padova
city: Palermo
country: Italy
facility: Università degli studi di Palermo
city: Roma
country: Italy
facility: Policlinico Universitario A. Gemelli
city: Torino
country: Italy
facility: A.O.U. San Giovanni Battista - Molinette
city: Eindhoven
country: Netherlands
facility: Dept. of Internal Medicine Maxima Medisch Centrum
city: Birmingham
country: United Kingdom
facility: Cancer Research UK Clinical Trials Unit (CRCTU) - School of Cancer Sciences - University of Birmingham
state: Edgbaston
Study officials:
affiliation: Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, Italy
name: Massimo Terzolo, MD
role: STUDY_CHAIR
affiliation: Department of Internal Medicine, University of Wuerzburg, Germany
name: Martin Fassnacht, MD
role: STUDY_DIRECTOR
affiliation: Medical Oncology, Department of Clinical and Biological Sciences, University of Turin
name: Alfredo Berruti, MD
role: STUDY_CHAIR
affiliation: Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave Roussy, Villejuif, France.
name: Eric Baudin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Internal Medicine, Máxima Medical Centre, Eindhoven, The Netherlands
name: Harm Haak, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1056/NEJMoa063360.