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.

Trial ID: 2022-500013-32-01
Protocol: ADIUVO2
Sponsor: Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia

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Diseases & Conditions

Adrenocortical carcinoma

Objectives

The primary objective of this study 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 recurrence-free survival (RFS) in patients with high-risk **adrenocortical carcinoma** (ACC) following initial surgical resection. This comparison is clinically relevant as it aims to determine the most effective adjuvant therapy regimen to prevent recurrence in high-risk ACC patients, potentially improving long-term outcomes.

Secondary objectives include:

Assessing overall survival.
Evaluating the effect of serum mitotane levels, disease stage, Ki67 index, and surgical resection margins on clinical outcomes.
Investigating the impact of early start (1-6 weeks from surgery) versus late start (>6 weeks from surgery) of adjuvant therapy on clinical outcomes.
Assessing quality of life.
Evaluating serious adverse events.

Participants

The clinical trial involves a total of **120 participants** diagnosed with **adrenocortical carcinoma** (ACC). The study population includes both male and female subjects, aged 18 years and older, who are considered to be at high risk of relapse following surgical resection of the primary tumor. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of ACC with a Weiss score of 3 or higher, and a high risk of relapse as defined by the ENSAT classification. The trial includes individuals with an Eastern Cooperative Oncology Group performance status of 0 to 2. Participants are required to have undergone perioperative imaging without evidence of metastatic disease and must be able to comply with protocol procedures. The study population is characterized by a diverse range of individuals, including those from vulnerable populations, and requires participants to use appropriate contraceptive measures during the study. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **mitotane** alone versus mitotane combined with **cisplatin**/**etoposide** in patients with high-risk adrenocortical carcinoma (ACC) following surgical resection. This is a randomized, low-intervention, phase III trial with an observational arm. The trial aims to assess recurrence-free survival (RFS) as the primary endpoint, with secondary endpoints including overall survival, quality of life, and the impact of various clinical parameters on outcomes. The trial is expected to conclude by December 2029, with recruitment having commenced in May 2023.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of ACC, high risk of relapse, and an Eastern Cooperative Oncology Group performance status of 0-2. Follow-up visits will occur every 12 weeks to monitor clinical outcomes through physical examinations, imaging, and laboratory assessments. The end-of-study visit will document the final outcomes, including any recurrence or completion of study treatments.

The expected duration of participant involvement is up to 24 months, depending on the treatment arm and individual response. Participants may be withdrawn from the study early due to reasons such as adverse events, withdrawal of consent, or non-compliance with protocol procedures. The trial employs a double-blind design to ensure unbiased results, with participants randomly assigned to either the mitotane alone group or the combination therapy group. The study will utilize validated tools, such as the EORTC QLQ-C30 questionnaire, to assess quality of life at specified intervals throughout the trial.

Treatment

The clinical trial involves the administration of several **experimental medications** and auxiliary treatments. **Mitotane** is administered orally in a pharmaceutical form identified as PHF00245MIG. The maximum daily dose is 3 grams, with a total treatment period of up to 24 months. This medication is of chemical origin and is used as a test product in the trial.

**Cisplatin** is administered intravenously, with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 60 mg/m², and the treatment period is up to 10 days. It is also of chemical origin and serves as a test product in the study.

**Etoposide** is another test product administered intravenously, with a pharmaceutical form of PHF675. The maximum daily dose is 100 mg/m², and the treatment period is up to 10 days. This medication is of chemical origin.

**Ondansetron** is used as an auxiliary treatment, administered orally in a pharmaceutical form of PHF00230MIG. The maximum daily dose is 16 mg, with a treatment period of up to 2 days. It is of chemical origin.

**Filgrastim** is administered as a solution for injection or infusion, with a pharmaceutical form of PHF802. The maximum daily dose is 5 µg/kg, and the treatment period is up to 2 days. This auxiliary treatment is of protein origin.

**Fludrocortisone** is administered orally, with a pharmaceutical form of PHF00245MIG. The maximum daily dose is 0.2 mg, and the treatment period is up to 24 months. It is of chemical origin and serves as an auxiliary treatment.

**Metoclopramide**, combined with D,L-lysine acetylsalicylate, is administered orally in a pharmaceutical form of PHF00169MIG. The maximum daily dose is 30 mg, with a treatment period of up to 2 days. This auxiliary treatment is of chemical origin.

Additionally, a **solution affecting the electrolyte balance** is administered as a solution for infusion, with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 2 liters, with a treatment period of 1 day. This auxiliary treatment is of chemical origin.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the evaluation of **recurrence-free survival (RFS)**. RFS is defined as the time from randomization to the documentation of radiological evidence of local or distant recurrence, or death from any cause, whichever occurs first. Patients will be censored at the date of their last evaluation if they are known to be alive and recurrence-free at that time.

Secondary efficacy endpoints include overall survival, which is the time interval from randomization to death from any cause. Additionally, the trial will assess the effect of serum mitotane levels, disease stage, Ki67 index, and resection margin status on clinical outcomes. These assessments will be based on physical examinations, complete blood counts with differential, serum chemistry profiles, endocrine assessments, and serum mitotane measurements at baseline and until adrenocortical carcinoma (ACC) recurrence. Cross-sectional imaging, such as CT with contrast medium, MRI of the chest/abdomen/pelvis, or FDG PET-CT, will be conducted every 12 weeks until ACC recurrence.

The trial will also evaluate the impact of early versus late initiation of adjuvant therapy on clinical outcomes using similar methods. Quality of life will be measured at baseline, 6 weeks, 6 months after the start of adjuvant therapy, and at the end of study participation using the EORTC QLQ-C30 questionnaire. 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 the end of treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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).

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Exclusion Criteria

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.