Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Ongoing, recruiting
Participants planned
240
Countries
3
Sites
26
Adrenocortical carcinoma
The primary objective is to compare the effect of adjuvant mitotane treatment alone (arm A) with that of adjuvant mitotane combined with four 21-day cycles of etoposide/cisplatin (arm B) on RFS in patients with high-risk ACC after initial surgical resection.
Key facts
- Sponsor
- Uppsala University Hospital, Universitaetsklinikum Wuerzburg AöR, Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia, Rigshospitalet, Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy, National Institute Of Endocrinology C.I. Parhon, Vall D Hebron Institute Of Oncology, Assistance Publique Hopitaux De Paris, University Hospital Centre Zagreb, Sao Joao University Hospital Center, Amsterdam UMC Stichting
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Neoplasms [C04]
- Trial duration
- 5 Jul 2024 → ongoing
- Decision date (initial)
- 2023-07-21
- Transition trial
- No
- Low-intervention
- Yes
- Rare-disease indication
- Yes
- Vulnerable population
- Yes
External identifiers
- EU CT number
- 2022-500013-32-01
- ClinicalTrials.gov
- NCT03583710
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Safety, Efficacy
The primary objective is to compare the effect of adjuvant mitotane treatment alone (arm A) with that of adjuvant mitotane combined with four 21-day cycles of etoposide/cisplatin (arm B) on RFS in patients with high-risk ACC after initial surgical resection.
Secondary objectives 5
- Assess overall survival.
- Assess the effect of serum mitotane levels, disease stage, Ki67 index, and surgical resection margins on clinical outcomes.
- Assess the effect of early start (1-6 weeks from surgery) vs. late start (>6 weeks from surgery) of adjuvant therapy on clinical outcomes.
- Assess quality of life.
- Assess serious adverse events.
Conditions and MedDRA coding
Adrenocortical carcinoma
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | PT | 10001388 | Adrenocortical carcinoma | 100000004864 |
Regulatory references
- Plan to share IPD
- No
| EU CT number | Title | Sponsor |
|---|---|---|
| 2022-500013-32-00 | Adjuvant mitotane vs. mitotane with cisplatin/etoposide after primary surgical resection of localised adrenocortical carcinoma with high risk of recurrence (ADIUVO-2 Trial): A pragmatic, randomised, low-intervention phase III, clinical trial with an observational arm. | Uppsala University Hospital |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 9
- Histologically confirmed diagnosis of ACC (Weiss score of ≥ 3). Lin-Weiss-Bisceglia system will be used for oncocytic ACC.
- High risk of relapse defined as: Stage I–III ACC (according to the ENSAT classification) within 90 days of surgical resection of primary tumour with curative intent with either microscopically complete resection (R0, defined as no evidence of microscopic residual disease according to surgical reports, histopathology, and perioperative imaging), microscopically positive margins (R1), or undetermined margins (RX, based on surgical or pathological reports without unequivocal evidence of metastasis in the perioperative imaging). Each participating centre will determine the pathological stages and resection margins; AND, Ki67>10% (to be determined by an experienced pathologist in each participating centre and preferably via quantitative imaging analysis).
- Perioperative imaging (CT with contrast, MRI of the chest/abdomen/pelvis, or FDG-PET CT) without unequivocal evidence of metastatic disease within 6 weeks before randomisation (ideally within 4 weeks). Patients with indeterminate non-specific nodules (<1 cm for soft tissue lesions and <1.5 cm in the short dimension for lymph nodes) will be permitted to participate in this study.
- 18 years of age or older
- Eastern Cooperative Oncology Group performance status 0–2
- Women of childbearing potential and men should use appropriate contraceptive measures to avoid pregnancy during therapy.
- Ability to comply with the protocol procedures
- Provide written informed consent
- [France] Affiliation with a mode of social security (profit or being entitled).
Exclusion criteria 15
- The time between primary surgery and randomisation is >90 days
- Renal insufficiency (estimated glomerular filtration rate [GFR]<50 mL/min/1.73m2) or significant liver insufficiency (serum bilirubin>2 times the upper normal range and/or serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST]>3 times the upper normal range). GFRs will be calculated according to the validated formula (MDRD).
- Impaired bone marrow reserve (neutrophils< 1000/mm3 and/or platelets < 100,000/mm3)
- Breast feeding
- Congestive heart failure defined as having moderate or severe systolic left ventricular dysfunction (ejection fraction<40%). The extent of cardiac testing will depend on the judgment of the local PI. In general, in patients with a history of cardiac disease, it is recommended to obtain a baseline two-dimensional echocardiogram as standard of care to document ejection fraction. In patients without prior cardiac disease, a baseline electrocardiogram (EKG) is sufficient if there is no evidence of acute ischemic changes or prior evidence of myocardial infarction. If EKG results are abnormal (ischemic changes, significant arrhythmia, or suggestion of prior myocardial infarction), a two- dimensional echocardiogram will be obtained to assess ejection fraction. Cardiac imaging and EKG may not be needed in patients randomised to mitotane who do not have prior cardiac history and have low suspicion for cardiac symptoms to reflect standards of clinical practice. Similarly, utilising cardiac imaging and EKG within the past 12 months is permitted if there is no suspicion for cardiac issues.
- Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would, in the judgment of the investigator, pose excess risk associated with study participation or administration of the involved drugs or that, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- Preexisting grade 2 peripheral neuropathy
- Patients that underwent previous or current treatment with mitotane or other antineoplastic drugs for ACC
- Patients that underwent previous radiotherapy for ACC
- Contraindication to mitotane, etoposide or cisplatin, as reported in the respective SmPC
- Gross residual disease after surgery (R2 resection)
- High suspicion for metastatic disease on perioperative imaging
- Patients that have undergone repeated surgery for recurrence of disease
- History of recent or active prior malignancy, except for cured non-melanoma skin cancer, or cured in situ cervical carcinoma, or breast ductal carcinoma in situ, or other treated malignancies where there has been no evidence of disease for at least 2 years.
- Protected adults (including individual under guardianship by court order) and persons deprived of their liberty by a judicial or administrative decision.
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- RFS will be defined as the time between the date of randomisation until documentation of radiological evidence of local recurrence, radiological evidence of distant recurrence or date of death from any cause, whichever occurs first. Patients will be censored at the date of their last evaluation in which they were known to be alive and recurrence-free, regardless of whether recurrence status was verified during that contact (e.g., phone contact).
Secondary endpoints 5
- Overall survival is defined as the time interval between the date of randomisation and the date of death from any cause.
- Assessment of the effect of serum mitotane levels, disease stage, Ki67 index and status of resection margins on clinical outcomes based on physical examination, complete blood count with differential, serum chemistry profile, endocrine assessment and serum mitotane measurement at baseline and until ACC recurrence. The effect will also be assessed using cross-sectional imaging (CT with contrast medium, MRI) of the chest/abdomen/pelvis or FDG PET-CT every 12 weeks until ACC recurrence.
- The effect of early vs. late start of adjuvant therapy on clinical outcomes will be assessed in a similar manner as above.
- Quality of life will be measured at baseline, 6, 12 and 24 weeks after the initiation of adjuvant therapy, after completing the 24m study treatment, and at the end of the 1y active follow-up using a validated quality of life questionnaire (EORTC QLQ-C30).
- Serious adverse events, grade 3 and above, will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0) until one year after end of treatment.
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 3
SCP100376572 · ATC
- Active substance
- Etoposide
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 100 mg/m2 milligram(s)/sq. meter
- Max total dose
- 100 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 10 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01CB01 — ETOPOSIDE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP26873719 · ATC
- Active substance
- Cisplatin
- Substance synonyms
- Cis-diamminedichloroplatinum, (SP-4-2)-cis -diamminedichloroplatinum, CDDP
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 60 mg/m2 milligram(s)/sq. meter
- Max total dose
- 60 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 10 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XA01 — CISPLATIN
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP177809 · ATC
- Active substance
- Mitotane
- Substance synonyms
- O,P'-DDD
- Route of administration
- ORAL USE
- Max daily dose
- 3 g gram(s)
- Max total dose
- 3 g gram(s)
- Max treatment duration
- 24 Month(s)
- Authorisation status
- Authorised
- ATC code
- L01XX23 — MITOTANE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Uppsala University Hospital
- Sponsor organisation
- Uppsala University Hospital
- Address
- Akademiska Sjukhuset
- City
- Uppsala
- Postcode
- 751 85
- Country
- Sweden
Scientific contact point
- Organisation
- Uppsala University Hospital
- Contact name
- Department of Endocrine Oncology
Public contact point
- Organisation
- Uppsala University Hospital
- Contact name
- Department of Endocrine Oncology
Universitaetsklinikum Wuerzburg AöR
- Sponsor organisation
- Universitaetsklinikum Wuerzburg AöR
- Address
- Josef-Schneider-Strasse 2, Grombuehl Grombuehl
- City
- Wuerzburg
- Postcode
- 97080
- Country
- Germany
Scientific contact point
- Organisation
- Universitaetsklinikum Wuerzburg AöR
- Contact name
- Internal Medicine and Endocrinology
Public contact point
- Organisation
- Universitaetsklinikum Wuerzburg AöR
- Contact name
- Internal Medicine and Endocrinology
Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
- Sponsor organisation
- Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
- Address
- Piazzale Spedali Civili 1
- City
- Brescia
- Postcode
- 25123
- Country
- Italy
Scientific contact point
- Organisation
- Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
- Contact name
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health
Public contact point
- Organisation
- Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
- Contact name
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health
Rigshospitalet
- Sponsor organisation
- Rigshospitalet
- Address
- Blegdamsvej 9
- City
- Copenhagen Oe
- Postcode
- 2100
- Country
- Denmark
Scientific contact point
- Organisation
- Rigshospitalet
- Contact name
- Departments of Nephrology and Endocrinology
Public contact point
- Organisation
- Rigshospitalet
- Contact name
- Departments of Nephrology and Endocrinology
Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
- Sponsor organisation
- Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
- Address
- Ul. Wybrzeze Armii Krajowej 15
- City
- Gliwice
- Postcode
- 44-102
- Country
- Poland
Scientific contact point
- Organisation
- Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
- Contact name
- Department of Nuclear Medicine and Endocrine Oncology
Public contact point
- Organisation
- Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
- Contact name
- Department of Nuclear Medicine and Endocrine Oncology
National Institute Of Endocrinology C.I. Parhon
- Sponsor organisation
- National Institute Of Endocrinology C.I. Parhon
- Address
- Bulevardul Aviatorilor 34-38
- City
- Bucharest
- Postcode
- 011863
- Country
- Romania
Scientific contact point
- Organisation
- National Institute Of Endocrinology C.I. Parhon
- Contact name
- Clinical Section of Endocrinology
Public contact point
- Organisation
- National Institute Of Endocrinology C.I. Parhon
- Contact name
- Clinical Section of Endocrinology
Vall D Hebron Institute Of Oncology
- Sponsor organisation
- Vall D Hebron Institute Of Oncology
- Address
- Calle Natzaret 115
- City
- Barcelona
- Postcode
- 08035
- Country
- Spain
Scientific contact point
- Organisation
- Vall D Hebron Institute Of Oncology
- Contact name
- Vall d’Hebron University Hospital
Public contact point
- Organisation
- Vall D Hebron Institute Of Oncology
- Contact name
- Vall d’Hebron University Hospital
Assistance Publique Hopitaux De Paris
- Sponsor organisation
- Assistance Publique Hopitaux De Paris
- Address
- 3 Avenue Victoria
- City
- Paris
- Postcode
- 75004
- Country
- France
Scientific contact point
- Organisation
- Assistance Publique Hopitaux De Paris
- Contact name
- Department of Endocrine and Metabolic Diseases
Public contact point
- Organisation
- Assistance Publique Hopitaux De Paris
- Contact name
- Department of Endocrine and Metabolic Diseases
University Hospital Centre Zagreb
- Sponsor organisation
- University Hospital Centre Zagreb
- Address
- Ulica Mije Kispatica 12
- City
- Zagreb
- Postcode
- 10000
- Country
- Croatia
Scientific contact point
- Organisation
- University Hospital Centre Zagreb
- Contact name
- Department of Endocrinology
Public contact point
- Organisation
- University Hospital Centre Zagreb
- Contact name
- Department of Endocrinology
Sao Joao University Hospital Center
- Sponsor organisation
- Sao Joao University Hospital Center
- Address
- Alameda Professor Hernani Monteiro
- City
- Porto
- Postcode
- 4200-319
- Country
- Portugal
Scientific contact point
- Organisation
- Sao Joao University Hospital Center
- Contact name
- Department of Endocrinology
Public contact point
- Organisation
- Sao Joao University Hospital Center
- Contact name
- Department of Endocrinology
Amsterdam UMC Stichting
- Sponsor organisation
- Amsterdam UMC Stichting
- Address
- De Boelelaan 1117
- City
- Amsterdam
- Postcode
- 1081 HV
- Country
- Netherlands
Scientific contact point
- Organisation
- Amsterdam UMC Stichting
- Contact name
- Department of Medical Oncology
Public contact point
- Organisation
- Amsterdam UMC Stichting
- Contact name
- Department of Medical Oncology
Sponsor responsibilities
- Article 77 compliance
- Uppsala University Hospital
- Contact point sponsor
- Uppsala University Hospital
- Article 77 implementation
- Uppsala University Hospital
Locations
3 EU/EEA countries · 26 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| France | Ongoing, recruiting | 55 | 20 |
| Germany | Ongoing, recruiting | 55 | 2 |
| Sweden | Ongoing, recruiting | 10 | 4 |
| Rest of world
United States
|
— | 120 | — |
Investigational sites
Assistance Publique Hopitaux De Paris
Oncologie médicale, 27 Rue Du Faubourg Saint Jacques, 75014, Paris
Institut Gustave Roussy
Unité d'oncologie endocrinienne, 114 Rue Edouard Vaillant, 94800, Villejuif
Centre Hospitalier Regional Et Universitaire De Brest
Diabétologie, endocrinologie, Boulevard Tanguy Prigent, 29609, Brest Cedex 2
Centre Hospitalier Regional De Marseille
Oncologie multidisciplinaire et innovations thérapeutiques, 265 Chemin Des Bourrely, 13015, Marseille
Hospices Civils De Lyon
Endocrinologie, de diabétologie et des maladies métaboliques A, 28 Avenue Du Doyen Jean Lepine, 69500, Bron
Centre Hospitalier Universitaire D Angers
Endocrinologie, Diabétologie et nutrition, 4 Rue Larrey, 49933, Angers Cedex 9
Centr Georges Francois Leclerc
Oncologie médicale, 1 Rue Professeur Marion, 21000, Dijon
Centre Hospitalier Universitaire De Toulouse
Oncologie digestive, 1 Avenue Du Professeur Jean Poulhes, Tsa 50032, Toulouse Cedex 9
Assistance Publique Hopitaux De Marseille
Endocrinologie, 147 Boulevard Baille, 13005, Marseille
Centre Hospitalier Universitaire De Reims
Endocrinologie, Diabétologie et nutrition, Rue Du General Koenig, 51092, Reims Cedex
Les Hopitaux Universitaires De Strasbourg
Endocrinologie, diabète et Nutrition, 1 Avenue Moliere, Bp 49, Strasbourg Cedex 2
Centre Hospitalier Universitaire De Nantes
Endocrinologie, Diabétologie et nutrition, Boulevard Du Professeur Jacques Monod, 44800, Saint Herblain
Institut De Cancerologie Strasbourg Europe
Oncologie médicale, 17 Rue Albert Calmette, 67200, Strasbourg
Assistance Publique Hopitaux De Paris
Endocrinologie et metabolisme, 27 Rue Du Faubourg Saint Jacques, 75014, Paris
Centre Hospitalier Universitaire De Nantes
Oncologie médicale, Boulevard Du Professeur Jacques Monod, 44800, Saint Herblain
Besancon University Hospital Center
Oncologie médicale, 3 Boulevard Alexander Fleming, Cs 81816, Besancon Cedex
Centre Hospitalier Universitaire De Poitiers
Endocrinologie, Diabétologie et nutrition, 2 Rue De La Miletrie, 86000, Poitiers
Centre Hospitalier Universitaire De Toulouse
Endocrinologie, 24 Chemin De Pouvourville, 31400, Toulouse
Centre Hospitalier Universitaire De Bordeaux
Endocrinologie – Oncologie endocrinienne, Avenue De Magellan, 33600, Pessac
Institut De Cancerologie De L Ouest
Oncologie médicale, 15 Rue Andre Boquel, 49100, Angers
Klinikum Der Universität München AöR
Medizinische Klinik IV, Ziemssenstrasse 1, Ludwigsvorstadt-Isarvorstadt, Munich
Universitaetsklinikum Wuerzburg AöR
Internal Medicine I, Josef-Schneider-Strasse 2, Grombuehl, Wuerzburg
Karolinska University Hospital
Tema Cancer, Eugeniavagen 3, 171 64, Solna
Sahlgrenska University Hospital-Vastra Gotalandsregionen
Oncology, Bla Straket 5, 413 46, Goteborg
Uppsala University Hospital
Department of Endocrine Oncology, Akademiska Sjukhuset, 751 85, Uppsala
Region Skane Skanes Universitetssjukhus
Oncology, Entregatan 7, 222 42, Lund
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| France | 2024-11-05 | 2024-11-05 | |||
| Germany | 2025-03-27 | 2025-04-01 | |||
| Sweden | 2024-07-05 | 2024-07-05 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 17 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | ADIUVO-2 protocol | 6.0 |
| Recruitment arrangements (for publication) | 2022-500013-32-01_RECRUITMENT-PROCEDURE_ADIUVO2 | 1 |
| Recruitment arrangements (for publication) | ADIUVO-2 Patientrekrytering | 1 |
| Recruitment arrangements (for publication) | ADIUVO-2 Recruitment Arrangements | 1 |
| Subject information and informed consent form (for publication) | 2022-500013-32-01_NIFC_patient-non-randomise_ADIUVO2 | 1.1 |
| Subject information and informed consent form (for publication) | 2022-500013-32-01_NIFC_RI_majeur_ADIUVO2 | 1.1 |
| Subject information and informed consent form (for publication) | ADIUVO-2 Patientinformation | 5.0 |
| Subject information and informed consent form (for publication) | ADIUVO-2 Patientinformation observation_redacted | 3.0 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF_GER_Exploratory_CLEAN | 1.0 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF_GER_Observational_CLEAN | 1 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF_GER_RCT_CLEAN | 5 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC_Cisplatin | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC_Etoposide | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC_Lysodren | 1 |
| Synopsis of the protocol (for publication) | ADIUVO-2 Synopsis_German | 5.0 |
| Synopsis of the protocol (for publication) | adiuvo2_resume-protocole-francais | 5-0 |
| Synopsis of the protocol (for publication) | ADIUVO2_Svensk synopsis | 5.0 |
Application history
8 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2022-09-13 | Sweden | Acceptable 2022-12-15
|
2022-12-19 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2023-10-10 | Sweden | Acceptable | 2023-11-16 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2024-06-19 | Acceptable | 2024-07-04 | |
| 4 | SUBSTANTIAL MODIFICATION | SM-3 | 2024-10-11 | Acceptable | 2024-10-29 | |
| 5 | SUBSTANTIAL MODIFICATION | SM-5 | 2024-10-17 | Sweden | Acceptable | 2025-01-13 |
| 6 | SUBSTANTIAL MODIFICATION | SM-4 | 2024-10-24 | Acceptable | 2024-12-09 | |
| 7 | SUBSTANTIAL MODIFICATION | SM-6 | 2025-08-08 | Acceptable | 2025-09-16 | |
| 8 | SUBSTANTIAL MODIFICATION | SM-8 | 2026-02-05 | Sweden | Acceptable 2026-04-16
|
2026-04-16 |